CA1045131A - Derivatives of 9-hydroxy-13-trans-prostenoic acid - Google Patents

Abstract

A B S T R A C T
Hydroxy substituted 15-deoxy prostanoic acids and derivatives there-of, having the general formula

Description

-p ~ :
~ 24,oog ' -~,' ~ ' `' ~, -.
'.' ' :' , ,"
1~)45~331L

This lnventlon relates to novel hydroxy substi-tuted 15-deoxy prostanoic acids and derivatIves as well :
as to lntermediates and methods for their preparatlon.
The novel compounds of this invention may be represented ;.` . -by the ~ollowing general ~ormula~
, .
O : ~

Rl R2 ... I ~ ;
~25 : ~ ;~
wherein~Rl ls selected rrom the group conslatlng of hy- .
drogen,~:hydroxy, lower alkoxy, tetrahydropyranyloxy, low- - :
er alkanoyloxy, ~ -hydroxy substituted lower alkoxy and ,! ~
t:e~trahydropyranyloxy:substituted lower alkoxy; R2 is ~ ;:
30 ~a molety selected from the group cQnslstlng of those of :.

- 2 :~ ,"

--` 1045~3~
,~ ~
1 the formulae:
. ~
l H2P l H2P
-CH=CH-CH-R' , 2 CH2-cH-R ~
-CH=CH-CH -R" and 2 CH2-CH2-R

wherein P is a hydroxy or triphenylmethoxy group, R' is a straight chain alkyl group having from 2 to 10 carbon atoms, or a straight chaln alkyl group ha~ing from 2 to 6 carbon atoms and havlng one branched alkyl group o~ ;
from 1 to 3 carbon atoms, and R" is a straight chain al-kyl group having rrom 2 to 10 carbon atoms and substitut-ed with a hydroxy or trlphenylmethoxy group, or a straight chain alkyl group having ~rom 2 to 6 carbon atoms and hav- ~ :
lng one branched alkyl group Or from 1 to 3 carbon atoms and substituted with a hydroxy or triphenylmethoxy group;
R3 1s selected from the group consl~ting o~ hydroxy, an alkoxy group having ~rom 1 to 12 carbon atoms and tetra- .
hydropyranyloxy; Y is a divalent radlcal selected from the group consisting o~ those of the rormulae: :

~
0 HO\ ,H H ,OH ~ I
A /c\ and : and Z is a divalent radlcal selected rrom the group con- ; :
slsting Or those Or the ~ormulae:

(CH2)~ ~ -(cH2)~-l-cH2- , -(CH2)n-CH- ~ ~ ;

~ :.
H2) -O-CH - an~ -(CH2)n-S-CH2-: 3 :
:

.. ..
~S~3~
, ~ .
1 wherein n is an integer ~rom 3 to 8 lncluslve, R4 is an alkyl group having up to 3 carbon atoms and R5 is an al-kyl group havin~ up to 3 carbon atoms, a ~luorlne atom or a phenyl group; and the moiety o~ the ~ormula:

o C
~
J 11_ Rl :
may be the divalent radical of the formula:
O '.,".,.`
C
H-ll lo X--C

when R3 is hydroxy or an alkoxy group having from 1 t~
12 carbon atoms. Suitable lower alkoxy and lower alkan~ ;
oyl groups contemplated by the present lnvention are those having up to four carbon atoms such as, for example, methoxy, ethox~, isopropoxy, sec-butoxy, formyl, acetyl, proplonyl, isobutyryl, etc. ~`
Also embraced within the scope o~ the present ;
inven~tion are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the preqent invention when R3 is hydroxy. The catlons comprised ln these salts in~clude, for example, the non-toxic metal cations such as the socllum ion, potassium ion, calcium ion, and mag-neslum lon as well as the organic amine catlons such as ; the;tri(lower alkyl)amlne cations (e.g., triethylamine) procaine, and the llke.
:

, .

. . . ~ .,, .;. , , ~ , . ,.. , , " ... .

513~
1 The novel compounds of the present invention are obtainable as yellow oils havlng characterlstlc ab-sorption spectra. They are relatively insoluble ln water but are relatively soluble ln common organlc solvents such as ethanol, ethyl acetate, dimethylformamlde, and the llke. The catlonlc salts of the compounds when R3 is hydrogen are, ln general, white to yellow crystalline solids havlng characteristic melting polnts and absorp-tlon spectra. They are relatively soluble in water, methanol, and ethanol but are relatlvely lnsoluble in benzene, dlethyl ether, and petroleum ether.
The prostaglandin~ are a family of closely re-lated compounds whlch have been obtalned from various anlmal tissues, and whlch stimulate smooth muscle, lower arterial blood pressure, antagonize eplnephrine-induced moblllzatlon of free fatty acids, and have other pharma-cologlcal and autopharmacological e~fects ln mammals.
See Bergstom et al., J. Biol. Chem. 238, 3555 (1963) and Horton, Experlentla 21, 113 (1965) and references cited 20 thereln. All Or the so-called natural prostaglandins are i derlvatlves of prostanoic acid:

CH2\ / C~2~ / CH

~ \ CH ~ CH2\ CH / 2\ CH2/ 2\ CH2 3 ,:
The hydrogen atoms attached to the C-8 and C-12 are ln trans conflguratlon. The natural prostaglandins represent only one o~ the posslble optical lsomers. The compounds ~ -;~ :
~ or this lnvention include all possible optical lsomers.
The novel compounds of the present invention ', ', ~ ~
. .

`: :

5~3'1 1 may be readily prepared from certain 4-substltuted cyclo- -pentenone intermediates whlch may be represented by the following general formula:

R~
` . .

~ Z-b-R~

wherein R'l is hydrogen, lower alkoxy, tetrahydropyranyl- : .
oxy, lower alkanoyloxy or ~)-tetrahydropyranyloxy lower alkoxy; and R'3 is tetrahydropyranyloxy or an alkoxy group .:
having ~rom 1 to 12 carbon atoms.

.: :, The 4-oxycyclopentenone intermediates may be :
readily prepared ~rom 2-carbethoxycyclopentanone in ac- :.
cordance wlth the reactlon schemes set forth in Flow6heets ~:~
A through D. In partlcular, the requislte 2-(~-carbeth-oxyalkyl)cyclopent-2-en-1-one intermediates (VIII) may :
., .- , .
be prepared in accordance with the ~ollowing reaction ~ .;-.
scheme: .
FLOWSHEET A ~
~. _ , .: , X~B2 )n~c~a (I~
:
: :
,-~

(CHajn-co~N ~(~Hz )n-co~a~g yl ' O

3 - 6 ~ ;
~, .
.:
;",: ' 10~513~
1 FLOWS~EET_A - Continued .: ' ¦ IV

V -~ ~C~)n~ao~a~ ~ (c~ )n~C~2Cz~g ~
O ~V~ Q-C~G~3 ~V~
O
, ' '~ ': " ' .
.....

~r ~: -CI~ln-CO2C2Hg ~ 5 Cu2 ).n~ C2C2 ~15 O (Vq~ (V~

'.. ,.:' wherein n is as hereinabove de~ined and X is iodo or :
bromo. In accordance with this reaction scheme, the cy-clopent-2-en-1-ones (VIII) are developed by first con~
vertlng 2-oarbethoxycyclopentanone (I) to the sodlum ~ .:
enolate thereo~ by means o~ sodium hydrlde in dimethoxy- -: :
ethane~and then treating~the sodium enolate wlth an ethyl ~:
-haloalkanoate (II). There i8 thus obtained the cor-resp~ondin~ 2-carbethoxy-2-( ~-carbethoxyalkyl)cyclopent-anone (IIX) which is then hydrolyzed and decarboxylated .~ .
to: af~ord the 2~ carboxyalkyI)cyclopentanone (IV). : :
: .
This acid is then esteri;~led with ethanol whereby the 2-( ~-carbethoxyalkyl)cyclopentanone (V) i.s obtalned.

30 ~The reaction conditions ror carrying out the above se- :

:

~: 7 :

--' ~
4513~ ::
1 quence Or reactlons are well known in the art. The con- -version Or the cyclopentanone (V) to the enol acetate (VI~ ls e~rected by heating with acetlc anhydrlde in the presence Or ~-toluenesulronlc acld. Preparation o~ the enol acetate (VI) usually requlres heatlng rOr a perlod Or ~rom about elght to thlrty-six hours. During this period~ lt is pre~erable to allow by-product acetlc acid to dlstill out ln order to ~orce the reactlon to comple- ;~
tlon. The bromlnation of the enol acetates (VI) to the 2-bromocyclopentanones (VII) is preferably carrled out ln a two pha~e system a~ ~ollows. A solutlon Or bromlne ln chloro~orm ls added to a rapldly stirred mixture Or a solutlon o~ the enol acetate (~I) ln chloro~orm and an aqueous solution Or an acid acceptor such as calcium car-bonate or soda ash. Thls additlon ls carrled out at 0--5C. over a period Or about ninety mlnutes stlrring ls contlnued ~or an addltlonal period o~ about half an hour to a ~ew hours, and the product (VII) ls then lsolated by standard procedures. The dehydrobromlnation o~ the 2-bromocyclopentanones (VII) is pre~erably carried out ln dlmethylrormamide with a mixture Or llthium bromide ~ ;
.
and lithium carbonate at the reflux temperature for a perlod of about 30 minutes to an hour or so. The so ~ormed cyclopent-2-en-1-ones ~VIII) are also isolated by standard procedures well known ln the art. Substitu-.
X (CH2)n C(R4)2~CH2~C2C2H5 for (II) ln Flowsheet A and carrying through the sequence of trans~ormations lllustrated therein ls productive o~ the rollowlng cyc-~lopent-2-en-1-ones (VIIIa):

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

~)45~3~
` ~ :

~ ( CH2 )n~C-CH2-C2C2H5 O h.4 (YIIIa) - 5 whereln X, n and R4 are as hereinabove defined.
The requlred cyclopent-2-en-1-one intermediates Or general structure (XVI), whereln the side-chaln has a lower alkyl group, ~luorlne atom or phenyl group alpha to the carbethoxy ~unction, may be prepared ln accordance ~-with the ~ollowing reaction scheme:

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

.: " ', .

. .

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

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

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

~30~
~ .
. . - .
: . ~' ' -- 9 _ , : '.
: ' .

~ [)4Sl;~î

FLOWSHEET B -(CH2)n -CO CeH~ ~ (C~{2)n -C02C2H, O (IX) N ~ (X) OCH, . ~ ~ I~ ,. .
10~ (CH2)n-O-S02-Y ~ CH2)n-OH

\ OCH (XII) ~ C~3 ~XI) , !
'.

CH2)n~0~SOa~Y CO2C~H, : :N ~ ~ (XII) : ~ Na- C- R, OCH~ ~ ~CO2C2E,~

20~ (XIII)~

R~ ~ fO2C~H:o H2)n-CH7Co2~H~ ~ CH2~)n-lC-R~
:0 ~ ~(XV) ~ ~ N . : C02C2H~
:~ ~OCH~. : :

(CH~) -CH-CO2C;~H~

:. , : ,, i .

1~513~
1 wherein n and R5 are as herelnabove defined, and Y is a methyl or ~-tolylradical. In accordance with this reac-tion scheme, the 2-(~J-carbethoxyalkyl)cyclopent-2-en-1--ones (IX), prepared as described in Flowsheet A ~or the preparation of (VIII) where is 2-7, inclusive~ are converted to the corresponding l-methoximino-2-(GJ-carbeth-oxyalkyl)-2-cyclopentenes (X) by treatment wlth methoxy-amine. Wlth the ring carbonyl function thus blocked it is possible to ef~ect a preferential reduction of the ester group by treatment with diisobutylaluminum hydride.
The resulting alcohol (XI) is converted to a mesylate -or tosylate derivative (XII), whlch undergoes displace-ment on treatment with the sodium salt o~ a diethyl sub- ~
stituted malonate (XIII) to provide the disubstituted y, ~;
malonate derlvatives (XIV). Hydrolysls and decarboxyla-tion as well as concomittant cleavage of the methoximino ~ -blocking group provides the desired 2~ carboxy-G)-sub-stituted alkyl)cyclopent-2-en-1-ones (XV)~ which are readily converted to the corresponding (XVI) by the usual 20 Fisher procedure. -The requisite 2-(~J-carbethoxy-3-oxa-alkyl)cy-clpent-2-en-l-ones (XXII) may be prepared in accordance with the reaction scheme o~ Flowsheet C, wherein n is as . .
hereinberore defined.

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

3 ' ~
!r.- :".,, ~, "
~. ',, '':
' .
~ 11 ~ '' " ' ~............................ ' ", '.
' "

FLOWSHEET C
.

~ (~H2~ G~2G~14 ~ (cHa)~ coec2~ :
O ( XVII ) N~
OCH9 -:
. ~ ,:
. . `', ,, ;"' ' 10 W~(cHz)n-o-cHecoeceH5 ~ (CH2)n-OH

N\ . (XX) \ (X~X) :

.

~
, (CH2) n-O-CN~G~II ~ (CHZ)n-O-cH2-co2c~H~
O (XXI): (XXII) : .
~
, . . .
:~In accordance with the reaction scheme shown in Flowsheet C, ~or the preparation Or the oxa derlva-~: tives tXXII), an appropriate 2~(~J-carbethoxyalkyl)cy-clopent-2-en-1-one (XVII) is converted to the correspond~
25 ing methoxime (XVIII), the ester function o~ which is .
then preferentially::reduced with dllsobutylalum~inum hy-drlde to afford th9 methoxime alcohol (XIX). The alcohol (XIX) ls converted on treatment with n-butyl llthium to ~ : .
the lithio alooholats, which thsn is O-alkylatsd by rs-: 30 action with ethyl bromoacetate to provlde (XX). Hydroly-.

:
: ::
- 12~
r .

04513~ ~
1 sls with acetone-aqueous hydrochloric acid furnlshes the deblocked keto-acid (XXI), which is then re-esterified with ethanol in the presence of ~-toluenesulfonic acid to give the required 2~ carbethoxy~3-oxa-alkyl)cyclo- :
pent-2-en-1-one (XXII). O-Alkylation can also be ac-complished by treatment of the lithio alcoholate o~ (XIX) with sodium or other metal salt of bromoacetic acid, in which case the free carboxylic acid corresponding to ,.~.,,.: ;,- ..
ester (XX) is obtained. Hydrolysls as ror (XX) provides the keto acid (XXI).
Some of the transformations involved ln the ~:
preparation of the 4-oxycyclopentenone intermediates are ~ :

set forth in the following reaction scheme: :
'~ , ' ', `~
''' "'' ,' '~' ' " ' ' " ' r ' :

.
':

' ' '," ' 1~5~3~

FLOWSHEET D
.
....

~ Z---R8 W Z!C-O-A
(XXIII ) ~ O (XX~) Br ~ O-(CH2)4-OH
~ Z-C-O-Rg ~ W R8 o (XXIV) O(XXVI) J, \\~ , ~( CH2~-~ \ RgO

~l Z'-C-O-R8 \ ~3~ Z' C-O-R8 O(XXVIII) \ O (XXVII3 ;~

R8=H \~

HO AcO

Z'-~-O-R~ Z_d-O-( XXX ) ( XXIX ) ~25 ~ ~ I z~ -ON~ z' C-~
:: 30 :: O (XXXI)o (XXXII) . ~ .
: ; ' ' .

. . .

:, . . .

l~S~3~
l wherein ~8 is hydrogen or lower alkyl, Rg ls lower alkyl, and Z' i~ as herelnabove derined for Z except that it ,., does not include the moie1;y: -(CH2)n-S-CH2-, and m ls an lnteger ~rom two to ~ive, lncluslve. Introduction of the f-oxy-runction into the 4-unsubstituted cyclopenten- -ones (XXIII) is accompllshed by ~irst halogenating the

4-position with an allylic halogenatlng reagent, prefer-ably N-bromosuccinimide. The resulting 4 bromocyclopen-tenone (XXIV) ls then solvolyzed for the introduction of the oxy function. This step is pre~erably carried out in the presence of a silver salt to ~acilitate the dis-placement o~ the halide ion. The particular 4-oxy deriv-ative that i8 rOrmed iS determined by the nature of the solvent system. Treatment of the 4-bromocyclopentenone 15 with sllver fluoroborate in water~acetone (ror solubility) ~
provides the 4-hydroxycyclopentenone (XXV). When the ^ -cyclopentenone ls a carboxylic acid (i.e. R8 = hydrogen), then this procedure provides (XXXI). When the solvent .. .
system ls water-tetrahydroruran, in addition to the 4-hy-droxy derivative there is also obtained the 4'-hydroxy-butyloxy derivative (XXVI), ~ormed by solvolysis with ;, .
tetrahydro~uran. When the solvent is only tetrahydro~uran `
then only the latter compound is rormed. Substltution Or tetrahydro~uran with alcohols, e.g., methanol, eth-anol, isopropyl, butanol and the like, provides the 4-al-koxycyclopentenones (XXVII). Wlth ethylene glycol or ; propylene glycol, etc. the correspondlng 4-(~J-substitut-ed hydroxy alkoxy) cyclopentenone (XXVIII) is obtained.

In the latter three procedures it is pre~erable to add a proton acceptor which will not react with (XXIV), ~br ex , . : ~ . .
.

. .

lU~5~L33L
1 ample, sym. collldine. When solvolysis is carried out with a silver lower alkanoate ln the corresponding lower alkanolc acid, such as the silver acetate-acetic acid system, the 4-acetoxy derivative (XXIX) is obtained.
Careful alkaline hydrolysis o~ thls product with potas-sium carbonate ln aqueous methanol provldes the free 4--hydroxy derivatlve (XXX~; further hydrolysls with barium hydroxide gives the free carboxylic acid (XXXI).
In general these procedures are operable with el~her the ~ree carboxylic acid or alkyl carboxylate, as desired. A particular alkyl carboxylate not provided by rormula (XXIII) can be obtained by hydrolysis to the acid and esterirication in the usual way, for example with the appropriate alcohol, or for a t-butyl ester ~;
with isobutylene. However, for the subsequent alanate con~ugate addition process lt is necessary to utilize a cyclopentenone wherein the carboxylic acid as well as all ~ree hydroxyl groups are blocked. A partlcularly use~ul ~ -blocking group for both functions is the tetrahydropyr-anyl group (see for example XXXI--~ XXXII) slnce this group can easily be cleaved wlth weak acid under condi-tions which do not disrupt the subsequently-prepared, relatively-unstable ll-oxy-9-keto system (~-hydroxy-ke-tone). Thu~, it is not possible to e~ect a satis~actory chemical hydrolysis Or an alkyl ester or o~ an ll-O al-. .
kanoyl group in an ll-oxo-9-keto prostanoic acid deriva-tive under conditions to which this system iq stable ;
(enzymatic hydrolysis is possible). 0~ course these ,: . -stability considerations do not apply in the "F" (9-hy-30~ droxy) serles. -. ...
~ .
:~ ~ ,''''.' "

;

~1~)4S~3~
1 The 9-keto-15-deoxy-13-trans-prostenolc acids and esters Or this invention, as deflned in the general ~ormula on page 1 above may be prepared from cyclopen-tenone (XXXVII) and the triphenylmethoxy substltuted

5 -lalkyne (XXXIII) as depicted in Flowsheet ~. In Flow- ~ :
sheet E~ R'l~ R'3 and Z are as hereinabove defined and R5 is a moiety of the rormulae: :

IH2o-c(c6H5)3 and -CH -R"' -CH-R' 2 10 wherein R' is as hereinabove deflned and R"' is a . :
straight chain alkyl group havlng ~rom 2 to 10 carbon at- ~ `
oms and substituted with a triphenylmethoxy group, or !~
a straight chaln alkyl group having ~rom 2 to 6 carbon ~ `~
atoms and havlng one branched alkyl group Or from 1 to : -15 3 carbon atoms and substituted with a triphenylmethoxy ~.
group. Also, R is a lo~er alkyl group o~ up to 4 carbon -atoms, R"l is as de~ined above ~or Rl except that it is .
not tetrahydropyranyloxy or ~ -ketrahydropyranyloxy lower : `-alkoxy, and R"3 is as defined above ror R3 except that , 20 it is not tetrahydropyranyloxy. ~ :

. . .

'.`. , ~. .

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

: ' , 17 - .:`` .
.:: , `, r~

13~L
FLOWSHEET E

CH3 - CH- CH3 CH H\ R~
H - C--C-Re +CH2 -A 1 -H >CHCH2-Al ~ \ H
(XXXIII) 7H2 CH9CH2 CH CH

(XXXIV) (XXXV) -,-i ' RLi ~ ~ ' .
R ' Li ~Z-C-R3 +CH-CH2-Al-R H
O C~3 1 ~ -CH2 .
( XXXVII ) CH\
CH~ CH3 (XXXVI) ~` Z G- ~ ~(z-r ~XXXVIII) ~ ~(XXXIX) ~ ; :

3~
: .:
~ -, .

' ' .5~3~
1 In accordance with the reactlon scheme of ~low-sheet E, the triphenylmethoxy substituted l-alkyne (XXXIII) is treated wlth diisobutylaluminum hydride (XXXIV). This reaction of the l-alkyne (XXXIII) with diisobutylaluminum hydride (XXXIV) provides the alane (XXXV) contalning the tra_s-double bond and is carried out in an inert solvent such as benzene, toluene, and the like at temperatures in the range of 40-60C. ~or ~`
several hours. It can also be carried out ln a solvent `
10 such as tetrahydrofuran, usually in an approximate 2:1 -I mixture with benzene or hexane; in which case the reac- ;;
tion requires somewhat more vigorous condltlons, usually treating at about 70-75C. for about eighteen hours.
The subsequent reaction with methyl or n-butyl lithium (R-Li) is preferably carried out in a mixture of the above solvents with an ether-type sol~ent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like.
This reaction is rapld and is preferably carried out at ~ :
0-10C. with cooling. The con~ugate 1,4-addition of the resultlng alanate salt (XXXVI) to the cyclopent-2-en--l-one (XXXVII) ls preferably carrled out at ambient , temperatures for a period of 12 to 24 hours. This reac-tlon is also best carrled out in an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the 11ke. The lntermediate alanate-enolate adduct ls then carefully hydrolyzed in situ with dilute hydro- ;
chloric acid with cooling, and the products (XXXVIII) -are isolated in the usual manner well known in the art. ~-Removal of tetrahydropyranyl blocking groups and of the trlphenylmethyl blo¢king group can then be accomplished ` " ' ' -- 1 9 -- `: , . ,~
,~

r~

~ S~31 .
1 by treating wlth weak acid. A preferred procedure in- ;
volves heating at 45C. for 3.5 hours ln a solvent sys-tem consisting o~ acetic acld:tetrahydro~uran:water in ;
the proportlon o~ 4:2:1. If (XXXVIII) is a tetrahydro-pyranyl ester, there is then obtalned the prostenoic acld (XXXIX, R"'3 - hydroxy).
All available evidence leads us to believe that the -CH=CH-R6 function introduced by the alanate process (see XXXVIII) occupies a position trans to the ll-oxy function (when R'l is not hydrogen). Simllarly, we are led to the conclusion that in the product (XXXIX) the two slde-chains attached to C8 and C12 are trans to each other. ~owever, we are not certain o~ this config-urational relationship ln product (XXXVIII) as lt is ob-tained directly from the alanate process. These productsmay have the slde-chalns in a trans- or cis-relatlonship or they may be a mixture contalnlng both the trans- and cis- isomers. This is indicated in the nomenclature of the compounds involved by the designation 8~. In order to ensure a trans-relationship in both (XXXVIII) and (XXXIX) these products can be submitted to condltions ~-known in the literature to equilibrate the cis-8-lso-PGE
to a mixture containing about 90% of the trans-product.
These condltlons lnvolve treatment with potasslum acetate ln aqueous methanol for 96 hours at room temperature.
The triphenylmethoxy substituted l-alkynes (A), the alanes (B) derived ~rom it and the alanate (C) are novel and useful intermediates for the synthesis of the compounds Or this invention are are to be considered a part Or this invention. In rormulae (A), (B) and (C) .. ..
: :,:

~ \
~Sl~
1 R6 and R are as herelnabove defined.

H-C_C-R~ H\ R~

(A) R C _ ~ I Li~`~ = C~
H-C-CH2- ~ H H-C-CH2-AIl_R

R-C-H R-C-H

R (B) (C) When the ll-oxy derivatlves (XXXVIII) or (XXXIX), preferably the ll-hydroxy derlvatives, are treat-ed with dilute acid it is posslble to effect elimination and the formation o~ the corre~pondlng ~ derivative (prostaglandins of the A type). A preferred procedure involves treatment in tetrahydrofuran:water (2:1) sol-vent 0.5N in hydrochloric acid for about seventy hours at ambient temperatures as set forth in the following ~ ;
reaction scheme. Under these conditions a tetrahydro-pyranyl ester w~ll undergo hydrolysis. See Flow~heet ~, below.
FLOWSHEET F -- --- . . . .
H0~ Rz R2 25~ ~ 0 ~ ~-C~

(XL) (XLI) wherein R2, R3 R"3 and Z are as hereinabove defined.
Those compounds of thls lnventlon embodying the -CH2-CH2-30 linkage at -C13-C14- may be prepared from the correspond- ;~

.,.: . , ' ' S~3~
l ing ~13 derivatives, obtained via the alante process, by catalytic reduction, pre~erably at low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.
The ll-oxy-9-keto derivatives of this inven-tion can be converted to the corresponding 9-hydroxy derivatives. If this conversion is efrected with sodium borohydride~ the product is a mixture o~ 9a- and 9~-hy-droxy derivatives (XLIII) and (XLIV) as set forth in the ~ollowing reaction scheme:
FLOWSHEET G
':~ . ',:
R2 R"

OH o Z-C-R
(XLII) (XLIII) (XLIV) ~;

20 When the reaction is carried out with lithium perhydro- ;
-9b-boraphenylyl hydride [H.C. Brown and W.C. Dickason, Journ. A~er. Chem. Soc., 92, 709 (1970)] the product is at least predominantly the 9a-hydroxy derivative (XLIII), wherein the 9-hydroxy group is cis to the side-chain at-tached to C8 and to the ll-oxy function). In accordance with accepted convention, an a-substituent at the 8-, 9-, or 12-positions is behind the plane o~ the paper whereas~a ~-substituent at these positions is in front of the plane of the paper. This is usually represented by a --- bond ror an ~-substituent, a -bond for a ~--, ,. ..

~, ', , ~, f'~

1~5~3~
~ ~ , 1 -substituent, and a~-bond where both are indicated.
Thus~ the 9-hydroxy derivatives may be variously repre-sented as follows:

C C ~ \C
H/ ~ H OH J ~
.:., -The preparation o~ the thia intermediates (XLVIII) and (IL), proceeds from the intermediate (XLV) 10 (XIX in Flowsheet C) which a~ter conversion to the ..
tosylate intermediate (XLVI) and reaction with the sodlum salt of ethyl mercaptoacetate ~urnishes intermediate .
(XLVII). Deblocking of (XLVII) with acetone-aqueous . . .
hydrochloric acid provides the keto-acid (XLVIII), which :

on re-esteri~ication with ethanol gives the required 2~ carbethoxy-3-thia-alkyl)cycloalk-2-en-1-ones (IL).

FLOWSHEET H ~ : .

20 ~ ~ ~ .:
~(CH2)n-0-so2~ cH3 ~(C~I2)n-OH ` ,', I~ ~ ; ' ' ~OCH3 ( XLVI ) ~OC~ (XLV) .~ ' -~ ! ~

(C1{:2)n-s-cH:~-co2-ci~s OCH3 ~XLVII) 1~ ~
.' ' . .~

: "
~ .

- 23 - ~ .
.
' ~ ' 1 FLOWSHEET H (Contlnued) (C~I~)n-S-CH2-CO~,H ,. . ~ ,,.

(XLVIII) `
~ ~ ".~; .:
: . ' ..
1~ .
~ ( CH2 )n-s-cH2 -C2 -C2EI5 ~, .........
(IL) ~
,~` - ' ,,.:',`
This invention also relates to new organic compounds related to the natural prostaglandins. More particularly, the novel compounds of thls lnvention are Il-oxy-9-keto(or 9-hydroxy)-13-trans-prostenoic acids, their homologues, analogues, derivatives and congeners.
Also included withln the scope of this inventlon are certain 4-oxycyclopentenone intermedlates useful for the synthesis of these novel compounds. The prostenoic acids Or the present invention may be represented by the : rollowing general formula:
O
,y ~, Z-C-o ~ ^

R O C,C~
-~ P~2 , -::
... .. .
wherein Rl is selected ~rom the group consisting of hy-drogen, lower~alkyl, lower alkanoyl, 4J-hydroxy lower alkyl, ~J-tetrahydropyranyloxy lower alkyl, and tetrahy-. ~ " . :

..

-5~31 - 1 pyranyl; R2 is selected from the group consistlng Or:
(a) a straight chain alkyl group having from 2 to 10 :~ .
carbon atoms, (b) a straight chain alkyl group having ~rom 2 to 6 carbon atoms and havlng one branched alkyl ~ .
group of from 1 to 3 carbon atoms, (c) a stralght chain alkenyl group having from 3 to 7 carbon atoms, and (d) :
a stralght chain ~ -haloalkyl group having from 3 to 7 ~
carbon atoms; R3 is selected from the group consisting .
o~ hydrogen, an alkyl group having from 1 to 12 carbon .
atoms, and tetrahydropyranyl; Y is a dlvalent radlcal se-lected ~rom the group conslsting o~:

o HO \ ,H H\ ,OH
/C / C \ and C

and Z is a divalent radical:

l4 (CH2)m ~ ~(CH2)n~lC-CH2- , R

: 20 -(CH2)n-CH_ or -(CH2)n-o_cH2_ whereln;m is an integer ~rom 3 to 9, incIusive, n ls an integer ~rom 3 to 6, incluslve, R4 ls a lower alkyl group having up to 3 carbon atoms, and R5 is a lower : .
; :alkyI group having up to 3 carbon atoms, fluorlne or phenyl; and the moiety : ~ O ~:
., ~ ~ H C
: ~ Clo ' 1~ . H ¦
/ lC~
R1 H '`

.: :

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

045~ 3~.
1 or the divalent radical O
/C~\ ' " ' H-C
Also embraced within the scope of the present invention are the non-toxi.c, pharmaceutically acceptable -salts of the novel compounds of the present invention when R3 is hydrogen. The catlons comprised in these salts inclu~e, for example, the non-toxic metal cations such as the sodlum ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as tri(louer alkyl)amine cations (e.g.~ triethylamlne),~
procaine, and the 11ke.
~ The novel compounds of the present invention , . .
may be readily prepare~d from certain 4-substituted cyc-; lopentenone lntermedlates which may be represented by the followin~ general formulae:

C~C)m~C~R3 2~5; whereln~m~and R3 are as;~derIned above; R6 is selected from the~group~oonsisting of halogen, hydroxy~ lower al- ;~
koxy, GJ-hydroxy lower alkoxy, lower alkanoyloxy, tetra- ;-hydropyranyloxy~,~ and ~J-tetrahydropyranyloxy lower al-koxy;~V~ls~a divalent radioal selected ~rom the group 0~consls~inx~or~

,.:

1 R~ R~
-(CH2)n-C-CH2- ~ (CH2)n~CH , and -(CH2)n-O-cH

wherein n, R4 and R5 are as defined above; and R7 is se-5 lected ~rom the group consisting of lower alkyl, ~J-hy- ~ -droxy lower alkyl, GJ-tetrahydropyranylo~y lower alkyl, and tetrahydropyranyl. :
The 4-oxycyclopentenone intermediates may be :
readily prepared from 2-carbethoxycyclopentanone in ac- ~ :
cordance with the reaction schemes set forth in Flowsheets ~ -A through D, hereinabove.
Certain of the novel compounds of the present invention may be obtained by the con~u~ate 1,4-addition of an alanate salt to a 2-substituted 4-oxy substituted cyclopent-2-en-1-oneS which method is also a part of the present invention. This novel procedure is set forth in the following reaction scheme: .
FLOWSH~ET L

CH3-ÇH-CH3 :: .
20 R~lO ~ + R ~51-C=C-R2 Z-C-OR'3 CH3-CH-CH3 O (XXXIII) (XXXIV~
. ~
~: ~ f' ,'.~
: 25 ~ ~ R2 .;.

R"lO~ ~ C~ ~Rz l1~ ~ C Cl ~Z-CO2H ~ ~Z-C-.OR'3 ~ ~ .
O ~(XXXVI) O O (XXXV) :~ 3O
, :. .

:
- 27 ~
' ' ' .:

~ ~09~513~
~~ 1 wherein Z and R2 are as hereinbe~ore defined; R' is a lower alkyl ~roup, prererably methyl or n-butyl; R'l is as defined above for Rl e~cept that it does not include hydrogen or an ~)-hydroxy lower alkyl group; R"l is as de~ined above ~or Rl except that it does not include tetrahydropyranyl or ~J-tetrahydropyranyloxy low~r alkyl;
and R'3 is as defined above ror R3 except that it does not include hydrogen.
The yields ~or the preparation o~ compounds (XXXV) by the con~ugate 1,4-addltion o~ an alanate salt (XXXIV) to a 4-oxy-2-substituted cyclopent-2-en-1-one (XXXIII) are usually good and a product uncontaminated wlth 1,2-additlon product ls usually obtalned. Further-more~ the trans~er o~ the alkene group is ef~ected with retentlon o~ the trans-con~iguration o~ the hydrogen at-oms attached to the double bond, and no reaction is noted at the ester function or funct~ons of (XXXIII). Another noteworthy aspect of thls reaction i3 that lt does not ;
requlre a catalyst. The alanate salts (XXXIV) are con-20 veniently prepared by the reaction of an approprlate --l-alkyne (R2-C~Hj wlth diisobutylaluminum hydride, fol-lowed by reactlon with a lower alkyl lithium derlvative, preferably methyl lithium or n-butyl lithium. Sultable l-alkynes which may be thus employed are, ~or example, l-butyne, l-pentyne, 1-hexyne, l-decyne, l-hendecyne, l-dodecyne, 3-methyl-1-butyne, l-heptyne, l-octyne, l-nonyne, 5-methyl-1-hexyne, 7-methyl-1-octyne, 7-methyl--l-nonyne, 3-methyl-1-octyne, 4-methyl-1-octyne, oct-5--en-l-yne, hept-5-en-1-yne, hex-4-en-1-yne, 5-chloro-1--pentyne, 6-chloro-hexyne, 7-chloro-1-heptyne, 8-chIoro-, . : .

l31 octyne, etc. The reaction o~ the l-alkyne with diiso-butylaluminum hydride cleanly provides the trans-double bond and ls preferably carried out in an inert solvent such as benzene, toluene, and the like at temperatures ln the range of 40C. - 60C. for several hours. The subsequent reaction with methyl or n-butyl lithium is preferably carried out in a mixture o~ the above solvent with an ether-type solvent such as diethyl ether, dlbutyl ether, tetrahydrofuran, and the like. Thls reaction is rapid and is pre~erably carried out at 0C - 10C. with cooling. The con~ugate 1,4-addition of the resulting al-anate salt (XXXIV) to the 4-oxycyclopent-2-en-1-one (XXXIII~ is prererably carried out at ambient temperatures for a period of 12 to 24 hours. Thls reaction is also best carried out in an ether-type solvent such as dl-ethyl ether, dibutyl ether, tetrahydroruran, and the like. The intermediate alanate-enolate adduct is then ~
carefully hydrolyzed in situ with dilute hydrochloric , acid with cooling, and the products (XXXV) are isolated in the usual manner well known in the art. Removal of tetrahydropyranyl blocking groups, if desired, oan then ;
be aooo~plished by treatlng with weak acid. A preferred ;
procedure involves heating at 45C. for 3.5 hours in a ! ', solvent system consistin~ o~ acetlc acid:tetrahydro~uran:-water in the proportion of 4:2:1. I~ (XXXV) is a tetra-hydropyranyl ester, there is then obtained the~ oxy-prostenoic acid (XXXVI).
..
All avallable evidence leads us to believe that the -G~I-CH-R2 function introduced by the alanate process :

3o (see XXXV) occupies a position trans to the ll-oxy ~unc-; - 29 -' :~ :

s~
1 tion. Similarly, we are led to the conclusion that in the product (XXXVI) the two side-chains attached to C8 and C12 are trans to each other. However, we are not certain that the configurational relationship in product XXXV) as it is obtained directly ~rom the alante process.
These products may have the side-chains in the trans-or cis-relationships or they may be a mixture containing both the trans and cis-isorners. This is indicated in the nomenclature of the compounds involved by the desig-nation 8~. In order to ensure a trans-relationship in both (XXXV) and (XXXVI) these products can be submitted '~
to conditions known ln the literature to equillbrate the cis-8-iso-PGEl to a mixture containing about 90% of the trans product. These conditions lnvolve treatment with potassium acetate in aqueous methanol for 96 hours at room temperatures.
When the ll-oxy derivatives (XXXV or XXXVI), ' preferably the ll-hydroxy derivatives, are treated with '-, dilute acid it is possible to effect elimination and the formation of the corresponding ~10 derivative (prosta~
glandins of the A type). A preferred procedure involves -~
treatment in tetrahydro~uran:water (2:1) solvent 0.5N
in hydrochloric acid for about,seventy hours at ambient ' ~' temperatures as set forth in the following reaction , '' .. .
scheme. (Under these conditions a tetrahydropyranyl ester w111 under~o hydrolysis.) (See Flowsheet M). ' ,'' FLOWSHEET M ,;~

H

HO ~ C' / C~c~R2 ,;
r ~ ~ ~ H ,~''' , `Z-C-OR3 ~ ~Z-C-OR"3 ~ , (XXXVII) (XXXVIII) ', - 30 ~

.~ ".... ~....
. .
.. . .

.5~31 1 wherein Z, R2 and R3 are as defined above and R"3 is hy-drogen or an alkyl group havlng from 1 to 12 carbon at oms. The compounds (XXXVIII) are also considered to be within the purview of the present invention.
The ll-oxy-9-keto derlvatives of this inven-tion can be converted to the corresponding 9-hydroxy derivatlves. If this converstion is effected wit~ sod-ium borohydride, the product ls a mixture of 9a- and 9~- ;
-hydroxy derivatives (XL and XLI) as set forth in the ~ ~ -following reaction scheme:
FLOWSHEET N ~;

R1 0~ ~1 O~D R10~ ~ Ra (XXXIX) ~Z-C-OR9 ~ "Z-ll-CR9 When the reaction is carried out with lithium perhydro~
-9b-boraphenylyl hydride [H.C. Brown and W.C. Dickason, Journ. Amer. Chem. Soc., 92, 709 (1970)] the product is at least predomlnantly the 9~-hydroxy derivative (XL, ~
wherein the 9-hydroxy group is cis to the side-chain at- -~. .. .
tached to C8 and to the ll-oxy functlon). In accordance with accepted convention, an ~-substikuent at the 9-po-sition ls behind the plane Or the paper whereas a ~-sub-stituent at the 9-posltlon is in front o~ the plane of the paper. This ls usually represented by a --- bond for an ~-substituent, a bond ~or a ~-substituent, and a 3 JJU~bond where both are indlcated. Thus, the 9-hydroxy ~ ;

, ~ - 31 -'~ ~09~5~3~L
` 1 derivatives may be variously represented as follows:

- C~/ \C/ ,~C~
H ~H H OH H OH
,'' This invention also relates to novel hydroxy substituted 15-deoxy-5-cis-prostenoic acids and esters as :
well as to intermediates and processes ~or their prepara- :
tion. The novel compounds o~ this invention embrace all .
the possible optical lsomers, diastereomers and enantio- : :
:: .
mers, racemates, and racemic mixtures represented by the :.
following general formula:

R O , . ~ ~CH - CH' (C~2 )n-C-R~

Ri~ CH = CH-~2 trans -: ~
,.': ~'"
20 wherein n is an integer ~rom 1 to 5, inclusive; R ls se- ::
lected rrom the group consisting Or hydro~en and lower ; :;:
.alkyl groups having up to three carbon atoms; Rl is se-lected from the group consistin~ o~ hydro~,en, hydroxy, .
tetrahydropyranyloxy, and tri(lower alkyl)silyloxy groups;
: 25 R2 ls a moiety selected ~rom the group consisting of : .
: ~ ~ those o~ the formulae: ~ :
~: ~ CH2P :
and -CH -R"
-CH-R' 2 wherein P is a hydroxy or triphenylmethoxy group, R~ is ~
30 a straight chain alkyl~or:alkenyl ~roup having from 3 to ~
, .-., ~: .. ..
: .
. .
- 32 - ~ ~ ~

~. ';.

r' 1045~3 ---- 1 10 carbon atoms, or a straight chain alkyl or alkenyl group having from 3 to 7 carbon atoms and having one or two branched alkyl groups from 1 to 3 carbon atoms, and R" is a straight chain alkyl or alkenyl Kroup having from 3 to 10 carbon atoms optionally substituted with an hydroxy or triphenylmethoxy group, or a straiKht chain alkyl or alkenyl group having from 3 to 7 carbon atoms and having one or two branched alkyl grouos of from 1 to 3 carbon atoms and optionally substituted with an hydroxy or triphenylmethoxy group, and a strai~ht chain ~-halo~
alkyl group having from 2 to 7 carbon atoms; R3 is se- ;
lected from the group consisting of hydroxy, alkoxy hav-ing from 1 to 12 carbon atoms, tetrahydropyranyloxy, and lower trialkylsilyloxy groups; Y is a divalent radical selected from the group consisting of those of the form-ulae: -O , H0~ C~ H ~ ,~

~ ,', ~, ' ' ' 20 and the moiety of the formula: ~
O
Il' .
...
: ~ , ,.
, -:
(A) R
may be the divalent radical Or the ~ormula:

~ ~ H ~ C

: : : H
~ 30:~

~: : :

~: - 33 -: ~ . .
~ ':, , ' --\ !f ~

'-~ lQ9LS131 , 1 with the proviso that when (A) is not (B) then at least one of Rl and R2 embraces an oxygen function. -Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds Or the present lnvention when R3 is hydroxy. The cations comprised in these salts include, for example~ the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and -~
magnesium ion as well as the or~anic amine cations such X~, as the tri(lower alkyl)amine cations (e~g., triethylam-ine), procaine, and the like. ;
The novel compounds of the present lnvention may be readily prepared from certain cyclopentenone in-termediates which may be represented by the ~ollowing general formula:

CHz cis (CH)-(cH~)n-c-R~3 ~ H H
R~

, ~. ,- .
wherein R and n are as hereinabove defined; R'l has all the posslbilities hereinabove defined for Rl except hy- ; -droxy; and R'3 embraces all the possibilities hereinabove deflned for R3 except hydroxy. The preparation of the 25 4-oxycyclopentenone intermediates is illustrated in j -Flowsheet I, which follows.

~ ~ ,''' "

~ 30 ~ ~
: '.
;, ~ .... :
~ - 34 -, .

10~5~L31 FLOWSHEET I

_,~ OH 6~) P' S ~< (C.,Hs):}P=CR(CH)(CH=)nCOO

'.' ' 7-- cis H--H
y\~CH-(CH2) -CO2H

R
(III ) : 1 . :

o ~ :

oF~FH-(cH2) -C02H ~' ;

, 2l3 :: (IV) ' [ ~ CH-(CH~j -CO,~

HO OH
., ~ .
~;.

, ~ ~0 .. .. .

: ~ : .. . :

3 5 _ `
~:'' ; ' r~ ~

)4S~3~ ~
,~ ~

FLOWSHEET I-continued :: -~CM-(CM2)n-C08H

, ~: :

O R
H-(cHz)n-co2H

~ (VII~
HO
. . .. . .
..-;, .

~H-(CH2)n-c08H `
H (VIII) ~ .
. ~ i , R ~: :

~ CH-(CM2)n-COaH
:~ :` 0 ' , : -, : .
OH ~ , ;
- : l , ..:

~ ~ :25 ~ ~: ~ `r ` ` ' :
:, . :
-vH - ( CH~I ~n - c-R ~

:~ : R ' l . .: .
( XI ) - 3 6 - :

~ 5~L3~L
1 In accordance with the above reaction scheme the 3,4-epoxylactol (I) [~.J. Corey and R. Noyori, Tetra-hedron Letters, 311 (1970)~ ls treated with the ylide (II) to give the 3,4-epoxycyclopentanol (III). Oxidation (for example with H2CrO4 H2S04-ether or Jones rea~ent) o~ (III) provides the epoxy ketone (IV), mild base treat- -ment of which results in the initial formation of the ;
4-hydroxycyclopent-2-en-1-one (VII) and the isomeric 3-hydroxycyclopent-4-en-1-one (VI) as a mixture. Further 10 treatment of this mixture with dllute base under mild ~
conditions results in the lsomerization of the 3-hydroxy ~;
isomer (VI) to the desired (VII). The transformation of the epoxy ketone (IV) to the hydroxycyclopentenones (VI) and (VII) and the isomerization of (VI) to (VII) may ~
15 take place through the intermediacy of the 3,4-diol (V). ~' It also is conceivable that isomerization of (VI) to (VII) procedes via the epoxy derivative (IV) or the cor- -responding ~-epoxlde (IX); it is further conceivable that (IV) procedes to (VI) and (VII) direct~y without the in-termediacy of (V). Another posslble intermediate for the isomerization of (VI) to (VII) is the corresponding diene (VIII). The preparation of (VII) is also possible vla the a-eDoxide series ~rom (IX) prepared via the a--epoxide corresponding to (I) and (III) such as (X) or most conveniently via a mixture o~ the a and ~ epoxides.
The hydroxy and acid function of the 4-hydroxycyclopent-enones (VII) are then appropriately blocked to give (XI, R'l ~ hydrogen). Appropriate blocking groups are tetra- -hydropyranyl, trimethylsilyl, dimethyl-isopropylsilyl, di-30 methyl-t-butylsilyl, and the like. ~ -.. ...
'.' ~:., "'. ' - 37 - `
':; ':

V45~L3~
1 The preparation of the requisite 4-unsubstitut- :
ed cyclopentenone intermediates can be accomplished by the sequences illustrated below in Flowsheets J and K, ` ~ .
wherein R and n are as hereinabove defined. `
FLOWSHEET J

~7\Co2c2Hs ~Cl-CH:CH2-OCHg >

(XII) ~XIII) ,: . . , :.

~1 CHzcH2oc~!3 ~ OzCzH
, CH2CH20C~9 "~
(XIV) (- ~) ., . '''` "`'`' ~ / ' " -., ~ Br ~ C~2GH20C~3 ~ C~2~120CH3 CH3~ 0 ~ (XVI) - O (XVII) 1 ~ , ~3\CH CH~OH ~ ~ C
C~2 \ H ~.;~ .:
XVIII) O
(XI~
', ~ ' .`` .
,~:,: ' ., : ~ 38 .: ;' ' :

:: : ` : :``;

~ ~0~5~31 LOWSHEET J - Continued (XIX) + ( C~iHs ~P-CH2 ( bEI) ( CH2 )nC - ~---- ~~- ~ -~~~ >
,' (XX) ' _ , '"'''''" ~' 0 ~CHz~ Cl~;\ (CH)(CH~)n-c~oH ~
o : :"
( XXI ) -H ~ , ~l~c~ll, Cl~:\(bH)(CH~) -C-OCH

( XXII ) ~ . . , -~0 ~ : .

:

,:
~5 : : ~ .

. . .
30 ~

.

- ~ :
. :, ,: :

-~ 10~513~L

1 In Flowsheet J above, the sequence wherein 2--carbethoxycyclopentenone (XII) is transformed to 2~
-hydroxyethyl)cyclopent-2-en-1-one (XVIII) is carried out in the manner described in Bel~ian Patent No. 786,215 (granted and laid open to 'Lnspection on January 15, 1973).
Methyl ether cleavage Or the correspondin~ 2~ methoxy-methyl)cyclopentenone is achieved by treating with boron tribromide. Oxidation of the alcohol (XVIII) with Collins reagent:chromium trioxide-pyridine complex in methylene chloride under anhydrous conditions [J.C~ Collins and W.W.
Hess, and F.J. Frank, Tetrahedron Letters, 3363 (1968)]~
provides the aldehyde (XIX), which is then treated in an-hydrous dimethylsulfoxide with the ylid prepared from an (~-carboxyalkyl)triphenyl phosphonium betaine (XX) and ;:: "
sodium hydride in dimethylsul~oxide (dimsyl sodium). The use of dimethylsulfoxide as a solvent for this reaction ~-leads to the predominant formation of the desired cis double bond derivative (XXI). The acid function in (XXI) can be esterified in the usual fashion; with diazometh-ane, thè methyl ester (XXII) is obtained.
An alternative~procedure is illustrated below in Flowsheet K, wherein R and n are as hereinabove de-fined.

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

~ ~ 30 ~ ~
: .

:
~ - 40 - ~ :
.. ,: ~ . .,, " .

,. ,:

.,, .,, . , j,, 1, ", ", , ,, , . " . ," ,, ~, . " ", ~ , . ........ ..... . . .. .. . .. .

'~~~ 10~513~L
~K :.

~ ~3 R
~ + ( C~iH5 ) 3P-CH2 - (~CH ~ - ( CH2 )n COO
0~
OH (XXIV) ( XXIII ) ' . . `
,' \ / ~.
~ I . .
I ' cis y~ CH2 - CH=CEI- ( CH) ( CH2 )nCOOH . . ,);
-HO R

( XXV) `' " ' ' l J~ c~s ~ CH2~ CH-(7H)(,CH2)ncOOH
:; Q R
~ . ~(XXVI) ' ;~

` ~ [~I ClS ~ .
\ CH2- CH=CH-(CH)(CH2)nCOOH

: 30 : . :
. (XXVII) .~ `

~ , - 41 - : :
,.".`

~0~5~31 1 In Flowsheet K above, the bicycllc hemiacetal (XXIII) [P.A. Grieco, Journ. Org. Chem., 37~ 2363 (1972)]
ls treated in dimethylsulfoxide with the ylld prepared rrom the triphenylphosphonium betaine (XXIV) and sodium hydride in dimethylsulfoxide (dimsyl sodium) to ~ive the l-hydroxy-3-cyclopentene (XXV). Oxidation with Jones re-agent gives the correspond:Ln~ ketone (XXVI), which on base treatment furnishes the required cyclopentenone (XXVII), which can then be esterified in the usual manner, e.g. to (XXII).
The trans-l-alkenyl side-chain is introduced in-to the molecule by the novel 1,4-con~ugate addltion pro-cedure involving treatment of the ester-ether blocked 4--oxycyclopentenone (XI) of Flowsheet I or the 4-unsubsti-tuted cyclopentenone ester (XXII) of Flowsheet J with alithio alanate reagent, such as (XXXI) or (XXXIV), pre-pared as illustrated below in ~lowsheet L. In this Flow-sheet, R, R'l, R'3 and n are as hereinabove described;
R"l ls hydrogen or hydroxy, R5 is a lower alkyl group (in 20 (R5)3~1 each value o~ R5 is not necessarily the same); ~ ;
R'2 is a moiety selected from the group consisting Or ~ ~

2 C(C6H5)3 .. ....
I and CH2-R"' wherein R' is -CH-R' as hereinabove defined, and R"' is a straight chain alkyl or alkenyl group having from 3 to 10 carbon atoms optionally substituted with a triphenylmethoxy group, or a stralght chain alkyl or alkenyl ~roup having from 3 to 7 carbon atoms and having one branched alkyl group o~ ;
from 1 to 3 carbon atoms, and optionally substituted with ~a triphenylmethoxy group, or a straight chain ~-halo al-.~ . . .
~ 30 kyl group havlng from 2 to 7 carbon atoms; R"3 is hydroxy : : '., ' ' ' ~ , ' :':

- 42 ~
'' '~ . 1' :lo~s~3~ - ~3_ 1 or an alkoxy group having from 1 to 12 carbon atoms;
and R"2 embraces all the values derined hereinabove for R2 except that it does not include triphenylmethoxy.
FLOWSHE~T L

H-C-C~R'2 ~ CH3-CH-CH3 (xx~III) CH2-Al-H
~CH2 CH

(XXIX) 1 0 . r ' ~ .

H trznsR'2 CH3` ~C 7C ~j CHCH2-Al ~ `H
C~9CH2 ~ .
CH
/ ~ \ ~ :

(XXX) .. ' ', ' .~ , .

H ~ ~ ,R~2 R51i : 20 I ~H :
tXxxII) ~ /

R5Li H t ans R'2 . ~ C=C ' \ ~ ~ CH-CH2~A /R H ~ : :
5 ~ : CH3 C~ : :
2 ~: :
- ~ .
CH9 ~ CH3 H ~ _R~z ~ (XXXI) . .
30 :~ Li ~ `H

(XXXIII) ~ ~3 ~C = C ~ 2 ~;

~(Rs)3Al Rs > . ~XXXIV~
' ',~

~ 5~3~

. . .
I.OWSHEET L- continued o . R O : .
~ F< ( CH ) - ( CHa ) - C-R ' 3 R ' l cis ~ (XXXI ) or (x~x~r) (XXXIV) R O ,: .:
~ ~~ CH= CH' ( CH ) - ( CH2 ) n ~ C -R ~ 3 r B'l ~ ~2 O ~¦ ( XXXVI ) ~ ~;

CH CH~( CH) - ( CH2 ) n- C-R"l ~~\Rn H
( XXXVII ) R
~; \~ ~CH CH~( CH) - ( CH2 jn-C~R 1 9 ` :~

H .

( XXXV~

,...

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

1.045~3 1 In accordance with the reaction scheme of Flow-sheet L, the requisite lithio alanage intermediates, e.g., (XXXI) or (XXXIV), are prepared from the l-alkyne (XXVIII) by one o~ two procedures. In one procedure, the l-alkyne (XXVIII~ is treated with diisobutylaluminum hydride (XXIX).
This reaction o~ the l-alkyne (XXVIII) with diisobutyl-aluminum hydride ((IX) provides the alane (XXX) contain-ing the trans-double bond and is carried out in an inert solvent such as benzene, toluene, and the like at temper-atures in the range of 40-60~. for several hours. It can also be carried out in a solvent such as tetrahydro-~uran, usually in an approximate 2:1 mixture with benzene or hexane; in which case the reaction requires somewhat more vigorous conditions, usually treatin~ at about 70--75C. for about elghteen hours. The subsequent reaction with methyl or n-butyl lithium (R5-L1) to giYe lithio al-anate (XXXI) is preferably carried out in a mixture of the ;
above solvents with an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like. This reactlon is rapid and is preferably carried out at 0-10C.
with coolin~.
In an alternative procedure the acetylene ;
(XXVIIIj is treated without isolation Or intermediates, ;~
with one equivalent of disiamylborane (prepared in situ 25 from diborane and 2-methyl-2-butene) and then with ex- -cess anhydrous trlmethylamine oxide followed by treatment with an aqueous solutlon of excess sodium hydroxide and a tetrahydroruran solution of excess iodine to give the ;~`

trans-l-alkenyl-l-iodlde (XXXII). Treatment of (XXXII) at low temperatures, preferably at about -30C~ to -78C.
: .
, ~' . .:

; :

', ~' ` ' ~5~31 1 in an inert solvent, eOg., hexane or toluene, with an alkyl lithium (R5-Li), e.g., butyl lithium, provides the trans-l-alkenyl lithium rea~ent tXXXIII). Treatment of this lithio derivative with a tri-alkyl aluminum prefer-ably trimethyl aluminum, furnishes the lithio trans--alkenyl trialkyl alanate (XXXIV). Treatment of a dial-kyl aluminum chloride with two molar equivalents of lithio reagent (XXXIII) gives the correspondin~ lithio bis(trans--l-alkenyl)-dialkyl alanate and treatment of an alkylal- -uminum dichloride with three molar equivalents of llthio reagent (XXXIII) affords the lithio tris(trans-l-alkenyl)-alkyl alanate. Each of the three types of alanates, can be utllized for 1,4-con~ugate addition, but reagents of the type represented by (XXXIV) are more economical and are preferred.
The con~ugate 1,4-additlon of the lithlo alan-ate, (XXXIV) or (XXXI), to the blocked cyclopent-2-en-1--one (XXXV) is preferably carried out at ambient temper-atures for a period of 12 to 24 hours. This reaction is best carried out in an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like; or in a solvent system such as benzene-hexane-diethyl ether. ;
The intermediate alanate-enolate adduct is then carefully .: . . .
hydrolyzed in situ with dilute hydrochlorlc acid with cooling, and the products (XXXVI) are isolated in the us-ual manner well known in the art. Removal o~ tetrahydro-pyranyl or trialkylsilyl blocking groups and, lf` present, Or the triphenylmethyl blocking group can then be accomp-lished by treatment with weak acid. A preferred proced-ure involves heating at 45C. for 3.5 hours in a solvent ~ "

. :
..

S~31 - 1 system consisting Or acetic acid:tetrahydrofuran:water in the proportion of 4:2:1. If (XXXVI) is a tetrahydro-pyranyl or trialkylsilyl ester, there is then obtained the prostenoic acid (XXXVII, R"3=hydroxy). Alkyl esters are not usually hydrolyzed by this procedure. In the ll-oxy-9-oxo-series saponification cannot be accomplish-ed chemically~ but can be achieved by enzymatic means, for instance with Ba~er's yeast in the usual manner. In the ll-deoxy series (Rl=hydrogen) or in the 9-hydroxy ser-ies chemical saponification is readily achleved.
All available evidence leads us to believe thatthe -CH-C~-R'2 function introduced by the alanate pro-- cess (see XXXVI) occupies a position trans to the ll-oxy function. Simllarly~ we are led to the conclusion that in the product (XXXVII) the two side-chains attached to C8 and C12 are trans to each other. ~owever, we are not certain of this configurational relationship in product (XXXVI) as it is obtained directly from the alanate pro-cess. These products may have the side-chain in a trans-or cis-relationship or they may be a mixture containing both the trans- and cis-isomers. I'his is indicated in .

the~nomenclature of the compounds involved by the desig-nation 8~. In order to ensure a trans-relationship in (XXXVI) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PG~
- 1 . ...
to a mixture containing about 90% of the trans product.

These conditions involve treatment with potassium acetate ;

in aqueous methanol for 96 hours at room temperature. ;

The triphenylmethoxy substituted lithio alanate . . , .: . .
reagent of type (XXXIV) and its precursors are novel and '' -5~L3~
1 useful compounds which are also embraced by this inven-tion. They may be defined by generic formulae A and B.

H tr n~ Rc ~ C = ~

' ' ~' ''' '''' "
. ., ,; .
In A and B R6 is selected from the moieties consisting Or fH2-O-C(C6H5)3 and -CH -R
-CH-R' 2 8 .
' :, :.' ,,:
wherein R' ls a straight chain alkyl or alkenyl group having from 3 to 10 carbon atoms, or a straight chain ~. .
alkyl or alkenyl group havlng from 3 to 7 carbon atoms :-.
and having one brarched alkyl ~roup of from 1 to 3 carbon :
atoms; and R8 is a straight chain alkyl or alkenyl group ~ .
having from 3 to 10 carbon atoms and substituted with one triphenylmethoxy group, or a straight chain alkyl or al~
kenyl group havlng from 3 to 7 carbon atoms and having ; .~:
: : ~ one or two branched alky3 groups of from 1 to 3 carbon ~ ;;
atoms and substltuted with a triphenylmethoxy group; R7 . : ~:
is a straI~ht chain lower alkyl group not necessarily the .
~ same for each use; and W ls selected from the group con~
: sisting of iodlne and lithium atoms. -:~
Although the trlphenylmethyl (or substituted : ~ triphenylmethyl), is es;sential for the ultimate introduc-tIon of a hydroxy substituted R2 moiety via lithio alan-~:, .' ' .
: - 48 _ "
.

~ ~0~5~3~L
1 ates prepared by the sequence (XXVIII) + (XXIX)-~(XXX)--~(XXXI), other blocking ~roups, e.g., tetrahydropyranyl, tri-alkylsilyl, a~ethoxy-lower alkyl, t-butyl, etc , are also useful in the sequence: (XXVIII) ~ (XXXII) >
(XXXIII)-~ (XXXIV).
When the ll-hydroxy derivatives (XXXVII, R"l-=hydroxy) or the ll-oxy derivatives embraced by (XXXVI), are treated with dilute acid it is possible to effect elimination and the formation of the corresponding ~lO
derivative (XXXVIII), prostaglandins of the A type. A
preferred procedure involves treatment in tetrahydrofuran:-water (2:1) solvent 0.5N in hydrochloric acid for about seventy hours at ambient temperaturesO Under these con-ditions a tetrahydropyranyl or trlalkylsilyl ester will undergo hydrolysis. (See Flowsheet L above).
The ll-oxy-9-keto derivatives, e.g., (XXXIX), of th~s invention can be converted to the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 20 9~- and 9~-hydroxy derivatives (XXXX) and (XXXXI), re- `
spectively, as set forth in the followin~ reaction scheme;

wherein R, R 1' R 2' ~"3 and n are as hereinabove de-fined.

' .:

.: .,.
: ' : : :

' : " ' ' '" :' 45~3~
O R

~, ~ CHiCH,( CEI) - ( CH2 )n-C-R" 3 R"~' ~ ~ R 2 .
H

XXXIX) \ .,, ',.
~H R o ~CE=CH~(c~)-(cR2)n-c-Rll3 \

" ~

I5 ~ ~
`.': ': ' ':
:
OH R O ~ ~:

~ cH=cH~( H) (CH2jn-c-Rll3 ; : :
I : I H
~ I . .:.
: 20 ~ I ~ "

~ (XXXXI) :~, hen the reaction is:carrled out with lithium perhydro-: ~ 25 ~-9~-boraphenylyl hydrlde [~I.C. Brown and W.C. Dickason, Journ. Amer. Chem. Soc.~92, 709 (1970)] the product is at least predominantly the 9~-hydroxy derivative (XXXX), ': .

wherein the 9-hydroxy group is cis to the side-chain at- ~ :
tached to~C8 and to the ll-oxy ~unction, ir present. In 30: accordance with accepted convention, an a-substituent at :: .:
~ .

: :~

, ;.

~ 5~3~
1 the 8-, 9-, 11- or 12-positlons is behind the plane of the paper whereas a ~-substituent at these positions is in front of the plane of the paper. This is usually rep-resented by a --- bond for an ~-substituent, a - bond for a ~-substituent, and a -v~_ bond where both are in-dicated.
The carboxylic acids of this invention can be readily converted to the various alkyl esters of this in-vention by treatment in the usual manner with the approp-riate diazoalkane.
The novel compounds of the present invention ;
have potential utility as hypotensive agents, anti-ulcer -agents, agents for the treatment of gastric hypersecre-tion and gastric erosion, agents to provide protection against the ulerogenic and other gastric difficulties as-sociated with the use of various non-steroidal anti-in- -flammatory agents (e.g., indomethacin, aspirin, and ~- ;
phenylbutasone), bronchodllators, anti-microbial agents, anti-convulsants, abortifacients, antidiarhheal agents, agents for the induction of labor, agents for the induc-tion of menses, rertility-controlling agents, central nervous system regulatory agents, salt and water-retention repulatory~agents, diuretics, fat metabolic regulatory agents, serum-cholesterol lowering agents, and as agents ~;25 for~the treatment o~ perlodontal diseases. Certaln Or ~ :
the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel . :, . .
compounds of this invention.

~Anti-Ulcerogenic Effect o~ Indomethacin The compounds of this invention provide protec-tion against the ulcerogenic properties of indomethacin.

,.

f~

'-`' 1~5:131 1 This assay was carried out in the following manner.
Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg./kg. of body weight) was administered by the subcutaneous route and one-half of the dose of the test compound was administered by gavage at the same time. After three hours, the second half of the test compound was administered also by gavage. Five -~
hours a~ter the administration of indomethacin the anl- ~;
mals were decapitated and the stomachs removed. The stomachs were washed wlth distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled water. The stomachs were spread out~ pinned on a cork and visualized under magni~ying glass for ulcers. The criterla for scoring of ulcers ;
was as previously reported. [Abdel-Galil et al., Brlt.
J. Pharmac. Chemotherapy 33:1-14 (1968)].
Score ; !

0 - Normal stomach } - Petechial hemorrhage or pin point ulcers 2 - 1 or 2 small ulcers 3 - Many ulcers, a few large 4 - Many ulcers, manyly large Control animals treated with indomethacin but not test compound consistently glve scores of about 3.0-=3.7. Control animals treated with nelther indomethacin nor test compound glve scores of about o . 5-0.8. l'he re-sults obta~lned in this assay with typical compounds o~
the present invent~ion are set forth in Table I below.
Compounds producing a score of 2.2 or lower are consid-. .
ered to be active. ;

;

~: ~ ', .' . . .

:

~0~5131 ~` 1 TABLE I

Total Oral dose;
mg./kg of body Compound weight Score Control lla-hydroxy-9-oxo--13-trans-prosten-5 oic a~~ 5 1.0 ___ 9-oxo-10,13-trans--prostenoic acid 50 1.7 ~~~

lla-(~-hydroxyethoxy)--9-oxo-13-trans-prost-enoic acid 100 1.8 --~

9-oxo-lla,16-dihydroxy-0.78 1.0 3.0 10 -5-cis,13-trans-prosta-dlenoic acid 0.39 2.0 3.

9-oxo-16-hydroxy-13--trans-prostenoic acid 50 1.2 2.3 9-oxo-16-hydroxy-pros-tenoic acid 50 1.3 2.3 The novel compounds of the present invention are also e~ective ~nhibitors of gastic acid secretion and of ulcer development in experimental anlmals, and thus are potentially valuable as agents ~or the control of gastric acid secretion and of gastric erosion and as anti-ulcer agents. Gastric acid secretion inhibitory - -, .:
action is usually measured by the "Shay rat" procedure(l~2) ~ - ~
;, . . .
with some modifications as follows. ~ -The rats (male, CFE straln) were starved ~or 48 hours (water was given ad llbitum) to permit evacua-tion Or stomach contents. On the morning o~ the experi-ment, under ether anesthesia, the abdominal reglon was , shaved and a midline incision (1-1 1/2") was made with a scapel. With the help of a closed curved hemostat the 30 duodenum was plcked up. Upon gettlng the duodenum into ;~

Shay et al., Gastroenterology 5~ 43 (1945) 2Shay et al, Gastroenterology 26, 906 (1954).
. ~
- 53 ~ ~
' .

S~31 1 view, ~ingers were used to pull the stomach through the opening, the stomach was then gently manipulated with ringers to rid stomach Or a~r and residual matter which were pushed through the pylorus. Two 5-inch sutures were drawn under the pyloric-duodenal puncture. A liga-ture, at the ~uncture, was ~ormed with one of the threads.
The second ligature was also formed but not tightened.
The test compound or the vehicle, usually 1 ml./100 g. body weight, were inJected into the duodenum as close as possible to the rirst ligature. After in-~ection the second ligature was tightened below the in-~ection site to minimize leakage. The stomach was plac-ed back through the opening into the abdominal cavity, the area of incision was washed with saline and the in-cision was closed with autoclips. (Ocasionally, in-stead of an intraduodenal in~ectiong animals were dosed by the oral or subcutaneous route. In the latter case, dosing was done thirty to si~ty minutes before the oper-ation).
Three hours later, the rats were decapitated and exanguinated, taking care that blood dld not drain into the esophagus. The abdominal cavlty was exposed by cuttin~ with scissors and the esophagus close to the stomaoh was clamped off with a hemostat~ the stomach was ~ -removed by cutting above the hemostat (the espohagus was cut) and between the two sutures. Extraneous tissue was removed, the stomach washed with saline and blotted on ~auze. A slit was care~ully made in the stomach which ~ was held over a funnel and the contents were collected ` -ln a centrifuge tube. The stomach was ~urther cut along : ~ , "''~
- 54 ~ ~

~ ~ .

: ``
5~L3i . . ~ . . .
1 the outside edge and turned inside out. Two ml. H20 were used to wash the stomach contents lnto the respect-ive centri~uge tube. The combined stomach contents and wash were then centrifuged out for 10 min. in the Inter-national Size 2 Centriruge (setking at 30). The super-natant was collected~ volume measured and recorded, 2 drops Or phenylphthalein indicator (1% in 95% ethanol) were added and the solution was titrated with 0.02N NaOH
(or with o.o4N NaOH when large volumes Or stomach con-tents were encountered) to p~ 8.4 (because Or usual col-oring of the stomach contents, phenolphthalein was only used to permit visual indlcation that the end point was near) and the amount o~ acid present was calculated.
Compounds inducing inhibition of gastric acid secretion o~ 20% or more were considered active. In a representative operation, and merely by way Or illustra-tion, the results obtained with this assay wlth typlcal compounds o~ the present invention are given ln Table II ...
... ~ .. .. .
below.
TABL~ II

; Intraduod~nal ..
dose, mg~/kg. Percent Compound of b~od~ wei~ht Inhibltion hydroxy-9-oxo-13-trans--prostenoic acid ~ 50 45 lla-(4-hydroxybuto~y)-9-; 25 -oxo-13-trans-prostenoic acid 50 42 9-oxo-10,:L3-trans-prosta-dienoic aold 50 31 ~ -9-oxo-16-hydroxy-13-trans prostenoic acid ~ 50 67 9-oxo-16-hydroxy-prosta 30 noic acid~ 50 58 : : . : : . .

~ 55 ~: ~ , ; ' `~ ' . ,.
....

.

~ ~5~3~ `:
1 TABLE II (Continued) Intraduodenal dose, mg./kg. Percent Compound of body weight Inhibition 9-oxo-20-hydroxy-13-trans--prostenoic acid 100 56 9-oxo-18/19-hydroxy-13--trans-prostenoic acid 100 28 9-oxo-1~-hydroxy 19,20--dinor-13-trans-pros-tenoic acid 50 21 Ethyl 9-oxo-18-hydroxy--19,20-dinor-13-trans--prostenoate 100 49 , Subcutaneous dose, mg./kg.
of body weight 9-oxo-lla,16-dihydroxy- 1.6 48 -5-cis 13-trans-prosta- 0.8 44 dienoic acid 0.4 35 ~, Bronchodilator activity was determined in gui-nea pigs against bronchospasms elicited by lntravenous in~ections of 5-hydroxytryptamine, histamine or acetyl-choline by the Konzett procedure. ~See J. Lulling, P.
Lievens, F. El Sayed and J. Prignot, Arzneimittel-Fors-chung, 18, 995 (1968)].
In the Table WhiCh fol lows bronchodilator ac-tivity for representative compounds o~ this invention ., , against one or more o~ the tree spasmogenic agents is expressed as an ED50 determined from the results obtain-ed wlth three logarithmic cumulative intravenous doses.

;
. , ~
.
' :':

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

1()~S~3~L
1 TABL~ III
_.= , ... ~

~ronchodiIator ACtIV~ (Konze~t~~ss~ys) ~ ~~
ED50, m~ g-. . . _ ~ enic Agent _ _ ~ .
Compound -tryptamlne histamine_ acet;vl-11 ~ -hydroxy-9-oxo-13- . ~ .
-trans-prostenoic acid 1.87 x 10 3 250 x 10 3 1.19 .~ .
11~ -(4-hydroxybutoxy)-9-; ~ r os -pr7~ t enoi~ __ 14 5 5 .5 .:
`.~ ' .' .~ :~'..
In Table IIIa below are set forth doses, not necessarily .
the minimum, which produce a signi~icant decrease in di- : ~
astolic blood pressure for typical compounds o~ the pres- .:
15 ent invention. ~' . ~:

,., , ,:, .

,` . ': ', ..:

, :',: .:

.- . .

. .
~ 2~

. .

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

: ~ ~ 57 , .

: : "`

4S~31 1 TAsLE IIIa . _ _ _ . _ . _ .. ._ HypotensiVe dose . (mg./kg~ of body Compound weight) _ `9-oxo-lla,16-dihydroxy-5--cis, 13-trans-prostadienoic ac~d 0.5 ~
9-oxo-lla316-dihydroxy 20- . --methyl-5-cis,l~-trans--prostadie~c acid ~~~ 0.5 ~ .-9-oxo-lla,16-dihydroxy-20- .
-ethyl-5-cis,l~-tr~ns- .:
-prostadienoic acid 0.5 :
9-oxo-lla,16-dihydroxy-20- . .
-nor-5-cis,13-trans- ..
-prosta~-noic-~a-cid 1.0 ;- `.
9-oxo-lla-hydroxy-15-hydroxy y~
methyl-5-cis,13-trans- . `- ::
-prostadienoic a~ ~ 2.0 ~:
9-oxo-11~,17-dihydroxy-5--cis,13-trans-prosta-dienoic ~ ~ 2.0 9-oxo-lla,16-dihydroxy-4(R)--methyl-5-cisJ13-trans--prostadienoic acla~~~ 2.0 : ~;.
9-oxo-lla,16-dihydroxy-20- -:
-methyI-5-cis,13-trans,18- .
-cis-prostadienoi~~~d~ 2,0 9-oxo-16-hydroxy-5-cis,13-:: ~ ~-trans-prostadienoic acid 2.0 ---; g-oxo-lla-hydroxy-5-cis,13- . --trans-prostadienoic acid 200 25 : ~ 9-oxo-lla-hydroxy-5-cis,l~- .
: -trans,17-cis-prosta~Ienoic 2.0 9-oxo-16-hydroxy-5-cis,10, ..
13-trans-prosta~trienoic acid1.0 9-oxo-5-cls,10,13-trans- .
:~ : -prostatrienoic acid~ 2.0 -~
~:~ 30 : .... _. = _ .
~; ~ : ;* ~ .

~ 58;

" ~O~S~L31 ~~ roncno~llator ACtiVity ~Iconzett ~ss~ys)- ~~ ~ -`:
ED50, mg.~kg-Spasmogenic A ent ~_ _ . . . ' .-5-hyd;^~ , Compound _ -tryptamine histamine choline 9-oxo-20-hydroxy-13-trans-117 x 10 3 30 X 10 3 2.16 ;--pro~tenoic acid ~ -~-9-oxo-18-hydroxy-19,20--dlnor-13-trans-prostenoic acid ~ 2.85 2.22 10.0 9-oxo~16-hydroxy-13-trans--prostenolc acid 277 x 10 ~4.6 X 10 ~ 455xlO ~ -9-oxo-16-hydroxy-prostanoic acid 22.7 x 10 3 477 x 10 3 ~ .-9-oxo-18/19-hydroxy-13-- ~ pro8tenoic acid 1.19 1.04 _ : .
-Baslc precursor compounds are known in the prior art as well as their methods of preparation. See . , for examp~le Belgian Patent No. 786,215.
This invention will be described ln greater de-tail in con~unction with the ~ollowing specific examples.
Example 1 Preparation of all cis-2-t6-carboxy 2-cis-hexenyl)-3 4--oxidocyclopentanol _ _ _ A solution of 1.42 g. (10.0 moles) of all-cis- ~ ;
-5-hydroxy-2~3-oxidocyclopentylacetaldehyde-~-Iactol (E.
,: ,:
J. Corey and R. Noyori, Tetrahedron Letters, 1970, 311) in 5 ml. of DMS0 is added to a stirred solutlon of the ~ Wlttlg reagent tE.J. Corey et al., JACS, 91, 5675 (1969)]
-~ prepared from~l3.3 g. (.30 mole) of 4-carboxybutyltri- ' ~ ~ 30 phenylphosphonium bromide (Example 8) 2.52 g. (.60 mole) `~
,:.
. ,:
.

: :

,, : . :.' : .
:, 45~31 `~ 1 o~ 57% sodium hydride dispersion, and 70 ml. Or DMS0 at 16C. during 1 minute.
The solution ls stirred at ambient temperature ~or 20 hours and poured into a stlrred mixture of methyl-ene chloride, lce, and hydrochloric acid. The or~anicphase is separated, and the aqueous phase is extracted with methylene chloride, saturated with sodlum chlorlde, ;
and extracted with ether. The combined organic extracts are partitioned with sodium blcarbonate. The aqueous basic extract is acidified with dllute HCl, saturated with sodium chloride, and extracted with ethyl acetate.
The extract ls washed with brlne, dried over magnesium sul~ate, and concentrated to give the crude title com-pound as an orange oil.
Exam~le ?
.. .. .
Preparation o~ all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4--oxidocyclopentanone :
. . , To a stirred solution o~ ca. 1.6 moles o~ ~;
crude all-cis-2-(6-carboxy-2-cis~hexenyl)-3,4-oxidocyclo-pentanol (Example 1) in 1.6 ml. of ether is added 1.6 ml.
of 4.0 N chromic acid in 4N sul~uric acld at 0C. during 9 minutes. A~ter stirrlng for 5 minutes at 0C. the so-lutlon is dlluted wi~th brine, ether, and ethyl acetate.
The organic phase is treated with isopropanol, washed 25 ~with~brine and dried over magnesium sulfateO Evaporation of the solvent gives the~sub~ect compound as an oil.
E ample 3 -:
Preparation o~f 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyc :~
lo~ent-2-en-1-one ;~A solution o~ 1.0 mmole o~ all-cis~(6-carboxy-60- .
:: .. :
!) , 3~
1 -2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 2) and 3.0 mmoles o~ sodium carbonate in 15 ml. Or water is al-lowed to stand at room temperature for 3 hours. The so-lution ls acidified with HCl, saturated with sodium ;
chloride, and extracted with ether. The extract is wash-ed with brine, dried over magnesium sulfate, and concen-trated to give a mixture of the title compound and the isomeric compound, 2-(6-carboxy-2-cis-hexenyl)-3-hydroxy-cyclopent-4-en-1-one. Further treatment of this mixture 10 with 10 sodium hydroxide at room temperature for 30 ~;
minutes causes the rearrangement Or the latter isomer to the t~tle compound, which ls isolated rrom baslc solution as above.
Example 4 Preparation Or 2-(6-carboxy-2-ci~-hexenyl)-4-hydroxycyc- -` -. lopent-2-en-1-one Treatment Or cis-anti-cis-5-hydroxy-2,3-oxido-cyclopentylacetaldehyde- ~ lactol (E.J. Corey and R.
Noyori, Tetrahedron Letters, 1970, 311), prepared~from ;
. .... .
the correspondin~ lactone and dlisobutylaluminum hydrlde as described ~or the preparatlon of the corresponding ;~
cis-~_-cis lactol, with 4-carboxybutyltrlph~nylphos-phonium-bromlde as deacrlbed ln Example 1 is productive of 2~-(6-carboxy-2- Q -hexenyl)-3a,4a-oxldocyclopentan-25 ~ ol whlch on oxidation by the method Or Example 2 provldes ~2~-~(6-carboxy-2-cis-hexenyl)-3a,4a-oxldocyclo-pentanone, which ln turn~on treatment with aqueous base by the~procedure o~ Example 3 furnishes the sub~ect com-~ . . .
pound.

: ~

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

l~S~L31 ,: .
,'~ 1 ~ , Preparation o~ 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclo-_ _ ~entanol _ :

A solution of 5.0 g. (35 mmoles) o~ 5-hydroxy--2,3-oxldocyclopentylaceta:Ldehyde-~-lactol (isomeric mix-tures; E.J. Corey and R. Noyori, Tetrahedron Letters, 1970, 311) in 25 ml. of DMS0 is added during 0.5 mlnute ~:
at 20C. to a stirred solution of the Wittlg rea~ent ~E.
J. Corey et al., JACS, 91, 5675 (1969); also ~xample 6]
and dimsyl sodium prepared from 23.5 g. (53 mmoles) of 4-carboxybutyltrlphenylphosphonium bromide, 6.1 g. ~140 .j -mmoles) of 57% sodlum hydrlde dispersion, and 230 ml. of :.
DMS0 (dimethylsulfoxlde).
The solution is stlrred at ambient temperatures .
~or 2 hours and poured into a stirred mlxture o~:methylene ;
chloride, lce, and hydrochloric acid. The reactIon mix~
ture is worked up as described ln Example 1, and the crude product is purlfied by dry column chromatography on silica gel to provide the title compound (mixture o~
two stereoisomers) as an ol:l, IR (~llm) 3450, 1710, and ~: 832 cm 1.
Example 6 Preparation Or 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyc-lopentanone _ _ 2~5 ~ A stlrred solution o~ 2.98 g. (13.2 mmoles) of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol (~x-amp}e 5):~in 66 ml. of~acetone is treated dropwise with ~ ~.
3.30 ml.~or 8N chromlc~acld in 8N M2S04 during 20 mln-utes~at -~10 to -5C. The:solution is stirred at -5C.
ror 10 minutes and treated~successlvely with a few drops ., ~ 62 . .: .

. ~ ~ : : : . .:
. :.
. ..

3~14513~
of isopropanol and 12 ml. of water. The mixture is filtered, :'1 . ' ' and the filtrate is concentrated, saturated with sodium chlo-ride, and extracted with ethyl acetate. The extract is washr ed with brine, dried over MgSO4, and evaporated to give an oil, I~ (film) 1740, 1710, and 840 cm Example 7 Preparation of 2-(6-carhoxy-2-cis-hexenyl)-4-hydroxycyclopent -2-en-1-one A solution (pH of 10.2-10.5) of 2.42 g. (10.8 moles) of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Ex-ample 6), 4.58 g.(43.`2 m~moles~ of sodium carbonate, and 216 ~, ml. of water is allowed to stand at room temperatures under nitrogen for 24 hours. The solution is acidified at 15C
with hydrochloric acid and extracted with ethyl acetate. The extract is washed with brine, dried over MgSO4, and evapor-ated to give an oil; IR (film) 1700 (carbonyl groups) and 1630 cm 1 (conjugated olefin; NMR 7011 (1~, 5.54 (2), and ~ :
495 (1) Example 8 Prepar;ation~of 4-carbo~ ybutyltriphenylphosphonium bromide A mixture of 103 g. of 5-bromovaleric acid and 152 g. of~triphenylphosphine in 400 ml~ of acetonitrile is refluxed for 48 hours, cooled, diluted with 100 ml. of ~ benzene and allowed to crystallize. The crystals are fil-tered, washed with benzene and ether, to yield colorless , ~material, m.p. 207-209C.

:

: . . ,;
. ~ :
~ 30 : ~ ~ ' ' ":
'' :. ' ~ ' , . . ~ 045~3~
, \ ~zr EXAM ~
Preparation of 4-tetrah,ydrop,yranyloxy-2-(6-carbotetrahydro-. . .
pyranyloxy-2-cis-hexenyl)cyc,lopent-2-en-1-one A vigorously stirred, ice-cold solution of 9.45 g. ' (42.5 mmoles) of 2-(6-carboxy-cis-2-hexenyl3-4-hydroxycyclo- ,-pent-2-en-1-one (Example 7) and 14.3 g. (170 mmoles of '~
dihydropyran in 212 ml. of methylene chloride is treated with 81 mg. (0.425 mmoles) of p-toluenesulfonic acid monohydrake. -After stirring for 5 minutes at 0C. and 60 minutes at 25C.
the solution is poured into a stirred mixture of 40 ml. of saturated brine, 40 ml. of saturated sodium bicarbonate and 80 ml. of water. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated to give an oil, ~;' ' ~ max (film) 1730 (ester carbonyl), 1710 ~ketone carbonyl), and 1030 cm 1 (tetrahydropyranyloxy groups).
.
. ' ., .
.. ,............................................. ~. -~ 6 b~ ` `
-, .
, , . ~ '' .
, 25, ~ ,;

~ ',': ,: ', . . . .
. '. ~
- - .-: ,~
,..
: ~ ~ . . '' , .
~; ~ - : . ''"' ,,.
, ~ ~04513~L :

EXAMPLE ~
Preparation of 4-(t'rimethylsiloxy)-2-(6-carbotrimethylsiloxy-. . _ .
-2-cis-hexenylcyclopent-2-en-1-one ~' To a solution of 5 g. of 2-(6-carboxy-2-cis-hexenyl- ~' -4-hydroxy-cyclopent-2-en-1-one (Example 7~ in'10 ml. of dry N,N-dimethylform2mide is added 5.4 g. of trimethylsilyl chloride in a nitrogen atmosphere. To the resu~ting solut~on ... . .
cooled in a tap water bath is &dded 5.05 g. of triethylamine ~' in 10 ml. of N,N-dimethylform~mide dropwise. The resulting mixture is stirred at 50C. in an oil-bath ~or 2 hours, then at ambient temperatures for 18 hours. Triethylamine ' ~
hydrochloride is removed by filtration and the filtrate is '`
. ^ ~
taken to dryness. The residual oil is further purified by distillation at high vacuum. ~ " '.' ~5 EXAMPLES ~ - ' . . , ~ , Treatment o~ the 4-hydroxycyclopent-2-en-1-ones ' "~
listed in Table 6 below with the indicated trialkylsilyl ' ' --chloride by the method described in Example ~ 'is productive of the bis-trialkylsilyl ether-esters of the table.
.

6 ~
. ., ,;
.:.. :,.
. . .: -.....
,:
: .
- '" :' .:: .. ..
; .. . .
..
3 o : !
- :.: . .

,.: ::
,,:

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

~L~4X~3~
~,, - 1 Example ~
Preparation_of l-oxa-2-hydroxy-bicycloE3.3 O]oct-4-ene A solution of 6.2 ~. (50 mmole~ Or th~ lactone of cls-2-hydroxycyclopent 4-ene-1-acetic acid [P.A.
Grieco, J. Org. Chem., 37, 2363 (1972)] in 350 ml. tolu-ene (drled over molecular sieves) is cooled to -75C.
and treated dropwise under nitrogen with 84 ml. of 0.89 M diisobutyl aluminum hydrlde (10.55 g., 74 mmole) over a period of about one hour maintalni~g the temperature ~;
at -74 - 2C. The resulting clear solution is stirred at -75~C. for two hours and poured with stlrring into a mixture Or 15 ml. of concentrated hydrochloric acid and 300 ml. o~ ice water. The mixture is stirred while warm-ing to room temperature. The layers are separated and -the aqueous layer 1s treated with salt and extracted with three small portions of ether. The comb-ined organ- -;
ic portlons are dried over sodium sulfate and evaporated at reduced pressure (75C. water bath) to yield the , product (homo~eneous by thin layer chromatography) as a 20 pale yellow mobile liquid. ,.~`~
Examp~

Preparation o~ l-hydroxy-2-~6-carboxy-2-cis-hexenyl)cyc-_ iopent-3-ene _ .
A solution of the sodium salt of dimethyI sul-;25 foxlde is prepared by stirring under nitrogen a mixture Or 160 ml. dry dimethyl sulroxide (dried over molecular sleves and~a ~ew pellets Or calcium hydride) with 6.0 g.

(0.25 mole~ of sodium hydrlde (prepared by washing 10.5 ` ;

g. Or 57~ sodium hydride dispersion in mineral oll wlth two 30 ml~ portions o~ hexane). The mixture is warmed 6 ~

~ ~- - . .

~045~3~
. ; .
~~ l with stirring at 75C. (oil bath) for 2.5 hours.
This solution is added ~uring about rive mln-utes to a solution under nltrogen- o~ 44 grams (O.l mole3 Or 4-carboxybutyltriphenylphosphonlum bromlde (~xample 8) in 180 ml. o~ dry dlmethyl sul~oxlde. The resultlng dark reddlsh brown solutlon is stirred for ten minutes, cooled to room temperature and treated with a solution of crude !~
l-oxa-2-hydroxy-bicycloC3.3.0]oct-4-ene (6.2 g., 50 - -~
mmole) (Example ~ ) ln 20 ml. o~ anhydrous dimethyl sul-foxide. The resultin~ solutlon is stirred 16 hours and then treated with 250 ml. of ice water.
Thls brown solution is extracted with two por- -tions of ether to remove neutral material then made strongly acidic with hydrochloric acid. The solution is -~
extracted into ~our lOO ml. portions of methylene chlor-lde. The combined methylene chlorlde extracts are wash-ed with water, then extracted with four lO0 ml. portions o~ 5% sodium bicarbonate. The combined aqueous extracts are washed with methylene chloride and m~de acidic to .

Congo Red wlth concentrated hydrochloric acid. The mix-I . .
ture ls extracted with three lO0 ml. portions of methylene chloride. The organic~extracts are combined, dried over sodlum su1fate and t;he solvent is evaporated at reduced ~pressure. The residue (an olly solid) is extracted sev-25 eral times with ether and the ethereal extracts are com- ~:
bined and~evaporated at reduced pressure to yield the cruds~product as a dark oll. The product ls purified by ~;
chromatography on silica gs1, elutlng with ether. The ; product is a colorless Iiquid. ;

~-- , . . .
3 o 6`~

. .

.

.... ~ .. .... . .... ~" .. . .

-~4~

Example 13 Preparation of 2-(6-carboxy-2-cls-hexenyl)cyclopent-3-en-1- ;
.. . .. ~
A solution of ~,2 g. of 1-hydroxy-2-(6-carboxy-2-cis-hexenyl)cyclopent-3-ene (Example 12) in 60 ml. of reagent acetone is treated dropwisè with a total of 6 ml, of 8N chro-mic acid in sulfuric acid at 0C. The oxidation is rather slow. The resulting mixture is dissolved in 200 ml. of water and the solution is extracted with six 50 ml. portions of ether. The combined ethereal extracts are dried over sodium sulfate and the solvent is evaporated at reduced pressure to yield the product as a yellow oil.
Example 14 Preparation of 2-(6-carboxy-2-cls-hexenyl)cyclopent-2-en-1-- _ _ one _ A solution of 3 g. of crude 2-(6-carboxy-2-cis-.
-hexenyljcyclopent-3-en-1-one (Example 13) in 100 ml. of aque-: .
ous sodium carbonate (pH: 10~ is stirred at ambient tem-peratures under nitrogen for 4 hours. The solution is acidi-,:
fied to Congo Red and extraoted into ether. The ethereal extracts are dried over sodium sulfate and evaporated at re-duced pressure to afford the product.

~ ~ Preparation of l-octyn-4;-ol ~ A suspension of 24.3 g. (1.0 mole? of magnesium in 90 ml. of dry ether is stirred at room temperature under ni-trogen wlth lOO~mg. of mercuric chloride, The reaction~is initiated by the addition of 2 ml. o~ propargyl bromide~and , maintained by the~ dropwise addition of a solution of 119.5 g.
30 ~ (1.0 mole) of propargyl bromide and 107.7 g. (1.25 mole) of valenaldehyde in 300 ml. of ~:
~, ~ 68~ _ ` ~04S131 dry ether. While the initial reaction is quite vigorous and is maintained at 30 only by cooling in an ice bath it may become necessary to heat the mixture to reflux tempPrature after about a third of the ether solution is added in order to maintain the reaction. Aft~sr the addition is complete the reaction mixture is refluxed until most the magnesium is dis-solvea ~several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml. of stirred ice-cold am-monium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml. por-tions of ether. The combined ether extract is washed with ~ -saturated sodium chloride solution, dried over magnesium sul-fate and filtered. Evaporation of the ether under vacuum leaves about 115 g. of yellow oil, which is distilled through a lS cm. Vigreaux column at 18 mm. The fraction boiling at 81-B2 is collected (36 g.) and the higher-boiling and lower- , boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a ~
, .:
trace of allene (5.1 u) and- gas-liquid partition c~romatogra-phy shows a purity of about 98% for the main fraction~

The product l-alkyn-4-ols of Table 11 below are prepared~by treatment of the aldehydes listed in ~able 11 ~; ;;with propargyl magnesium bromide by the procedure described `~

25~ ~o~e~in Example~15.

, ~

:: ' ~ : -: ' ' ~ - ~

_ 6~ _ ~ :~ : : :

~ .

_ _ Product Example Starting aldehyde l-alky~-4-ol 16 n-hexaldehyde ~-nonyn-4-ol 17 n-heptaldehyde 1-decyn-4-ol 18 n-butyraldehyde 1-heptyn-4-ol 19 3 cis-hexenalde- 4-hydroxy-6-hy~ cis-ene-l-non-yne _ - ............... _........ . : :
*M. Winter, Helv. Chim. ~cta, 46, 1792 (1963).
Example 20 Preparation of 4-Triphen~lmethoxy-l-octy;ne ~ -A mixture of 10 g. (o.08 mole) of 4-hydroxy-1--octyne ~L. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 ....
(1957), also Example 15] and 30.75 g. (0.09 mole) of triphen- ~
~ . .
15 ~ ylmethyl bromide in 85 ml. of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed suc-cessively with ice cold 2% hydrochloric acid, saturated sodi~
: .
um chlorlde solution, drled wi~th magnesium sulfate, and taken ~ -~
~20~ ~ ~to dryness. Column chromatography of the residue on Flori-sLl~ affords an oil; ~ max. 3.01, 4.72 (acetylenic hydrogen), -, : . . .
6.28,9.65~and~ 14.25 ~ (triphenylmethoxy groupj.
Ex mple 21 ; PreparatLon of 4-Triphenylmethpxy-l-hexyne 25~ A stirred solution~Qf 9.~1 g. (0.10 mole) of 4-hydroxy-l-hexyne~and 33.5~g.~(0.12 mole) of triphenylmethyl chloride~in~100 ml. of dry pyridine is heated at re~lux for 2~hours.~ The cooled mixture~i treated with water and ex-tracted~wlth ~a hexane-ether mixture. The extraat is washed ~ ;
30~ successively wlth water and saturated sodium chloride solu- `

.

~LOq~5~3~
., .
tion, dried over magnesium sulfate, and concentrated. Colum~
chromatography of the residue on Florisil~ gives an oil max. 3290 (acetylenic hydrogen), 1600,1030 and 705 cm (tri-phenylmethoxy group).
Examples 22-29 The triphenylmethoxy substituted l-alkynes listed ;
in the table below are prepared by the method of Example 20 from triphenylmethyl bromide and the corresponding hydroxy substituted l-alkynes, appropriate literature references to ~' which are provided in the table.

., : .
_ . . . _ _ ............. - .:
References to starting Product triphenyl-hydroxy substituted 1- methoxy substituted ;
Exa~ple alkYne l-alkvne , ~ , ._. _ .-22 Reference 1 4-triphenylmethoxy-l-pentyne 23 Reference 1 4-triphenylmethoxy-(Example 18) 1-heptyne - 24 Reference 1 4-triphenylmethoxy-5-methyl-1-hexyne Reference 2 4-triphenyImethoxy-(Example 16) ~ l-nonyne 26 Reference 3 4-triphenylmethoxy-(Example 17) l-decyne 27 ~ Reference 10 4-triphenylmethoxy-~ 7-methyl-1-octyne ~
28 ~ Reference 10 4-triphenylmethoxy- `
5-ethyl-1-hep~yne - 25 ~ ~ ~
; 29 ~ Ex~ample 19 4-triphenylmethoxy--6-cis-ene-1-nonyne . __ _. _ .
:
References: ~ ~
1. G. Fontaine~èt al., Bull. Soc. Chem. France, 1447 (1963).
~ 2. S. Abe and K.;Sato, Bull. Soc. Chem. Japan, 29, ~7i ., , . .. .,. , . , . , . . , ., . , ~.. . . . . . . . . .. . .

5~3~
88 (1956); Chem. AbstrO ~ 50, 13737 (1956).

3. L. Crombie and A.G. Jacklin, J. Chem. Soc., 1622 (1957); 174l0 ~1955).
4. R~ Paul and S, Tehelitcheff, Compt. rend., 232, 5. C. Crisan, Ann. Chim. (Pàris), ~13]1, 436 (1956).

6. R. Riemschneider, G. Kasang, and C. Boehme, Mon-tashefte Chem, 96, 1766 (1965).

7. Ames, J. Chem. Soc. (C), 1556 (1967).

8. L. D. Bergel' son et al., Zh. Obschie Khim., 32, 58 (1962); Chem. Abstr., 57, 14930a (1962)

9. N.V. Egorov and AoS~ Atavin, Chem. Abstr., 71, 61473u ~1969).

10. Nobuharra Akio, Agr. Biol. Chem. ~Tokyo), 32, 1016 ~1968); Chem. Abstr., 70, 3219j (1969).

11. J. Cologne and R. Gelin, Bull. Soc. Chem., France, 799 (1954).
Ex-ample 30 ~ .: ., To a stirred suspension of 600 g. of triphenylphos-phine in 2000 ml. of acetonitrile, under nitrogen atmosphere is added dropwise 118 ml. of bromine at a temperature not ~ exceeding 35C. After stirring for an additional hourl the ~supernatant llquid is decanted and taken to dryness. The solid residue is combined with the previous solid with 1500 ml. of dimethylformamide. The suspension is stirred at -20C.
and a solution of 200 g. of 1-octyn-3-ol in 300 ml. of di-:: :
methylformamide is added in three portions. The temperature is allowed to warm up slowly at 20bC. After three hours the ; solution is extracted with three 1600 ml. portions of petro- -leum ether (b.p. 30-60). The combined extracts are washed with saturated sodium chloride solution, saturated sodium -: : . .
bioarbonate solution, and finally with saturated sodium chlo~

ride solution, dried with anhydrous magnesium sulfate and _ 7~
~ ''~' ' ~ ' .
::
' , , ~ ! " . ' , 0'1~iL31 taken to dryness (bath 30-35C.). The residual oil was dis-tilled to give 117 g. (39%) of product, b.p. 66-68/9mm.
Example 31 Preparation of- l-iodo-4-triphenylmeth~x~-tra;ns-l~octene -- . .
To a stirred suspension of 1.78 g. (0.074 mole) of sodium borohydride in 200 ml. of dry glyme at -5C. under nitrogen is added 15.8 g, (0.22 mole) of 2-methyl-2-butene and 16.2 g. (0.11 mole) of boron trifluoride etherate, and the mixture is stirred for 2 hours at -5 to 0C. A solution 10 of 37'.5 g. ~0.10 mole) of 4-trityloxy-1-octyne (Example 20) in 50 ml. of glyme is added to the cold solution during 5- -10 minutes, and the solution is allowed to warm to 20 du~ing 1.5 hours. The reaction mixture is cooled to 0C., and 30 g.
~0.4 mole) of dry trimethylamine-N-oxide is added during 5 I5 minutes. On removing the cooling bath the temperature rises to 40C., and the mixturè is kept between 30-40 for 1.5 hours. The suspension is poured rapidly into 1 liter of ice cold 15% sodium hydroxide solution during good stirring and a solu~ion of 80 g. of iodine in 200 ml. of tetrahydrofuran is ~ added immediately. Stirrin~ is continued for 30 minutes without further cooling and the organic layer is separated.
The aqueous layer is extracted with three 200 ml. portions of ether and the combined organic layers are washed successively with water, 5% sodium thiosulfate solution and saturated ~; 25 ~ sodium chloride, dried over~magnesium sulfate~ filtered and .:
~ evaporated to yield 50 g. ~f yellow oil. The bulk of the :: ~ : .
oil is dissolved in hexane andj after decantantation from a gummy solld~the hexane solution is percolated through a 5.1 c~. dlameter~column of 1500 g. of alumina with additional ~hexane. ;Fractions containing the desired product are con-5~.31 . .
centrated to a pale yellow oil (33 g.) which has n.m.r. and infrared spectra characteristics of the desired product.
Ex~ples 32-40 Treatment of the triphenylmethoxy su~stituted 1-alkynes listed in Table 14 be]ow with disiamylborane, pre-pared in situ from 2-methyl-2-butene, boron trifluoride and sodium borohydride, follo~ed by trimethylamine N-oxide, and then sodium hydroxide and iodine -- all by the procedure de-scribed in Example 31 furnishes the product triphenylmethoxy substituted l-iodo-l-trans-alkenes of the table.

: .
.. ~ _ ... _ . . ._ ,. _ ..
Starting triphenyl methoxy Product l-iodo-tri- ;
substituted l-alkyne of phenylmethoxysubsti- ~`
Example Example tuted-l-trans-alkene v. .__ ._ ~._ , 32 21 1-iodo-4-triphenyl-methoxy-l-trans--hexene 33 22 1-iodo-4-triphenyl-methoxy-l-trans--pentene 34 23 1-iodo-4-triphenyl-methoxy-l-trans--heptene 24 1-iodo-4-triphenyl methoxy-5-~ethyl-1--t _ -hexene 36 25 1-iodo-4-triphenyl-methoxy-l-trans- ~ ;
-nonene 37 26 1-iodo-4-triphenyl-methoxy-l-trans--decene 38 27 1-iodo-4-triphenyl- ~ ;
methoxy-7-methyl-1-trans-octene 39 28 1-iodo-4-triphenyl-methoxy-5-ethyl-1- --~ ;
-t -heptene 29 1-ioda-4-triphenyl- .5 ii methoxy-l-trans,6-cis-~onadiene . - : . ~....... . ~ - ~.. ~ _.,. _ ... ,.
~'.' '.~: '' EXAMP~E 41 Preparation of 9-oxo-lla,16-dihydroxy-5-cis; 13-trans-prosta-dianoic acid To a stirred solution of 26.8 g.~slm moles) of 1--iodo-4-triphenylmethoxy-trans-1-octene (ExamPle 31) in 50 ml.

of toluene is added 26.3 ml. o 1.9 ~ n-butyllithium in hex-ane at -70. After the addition the solution is stirred for 60 minutes at -40. This solution containing 4-triphenylmeth--oxy-trans-l-octenyl lithium is treated with 26.8 ml. of 1.45 .
M trimethylaluminum in hexane at -40, and the resulting sol-ution is stirred at 0 for 20 minutes.
To the above solution containing lithio trimethyl--(4-triphenylmethoxy-trans-1-ocbenyl)alanate is added a sol-ution of 16.7 g.~42.5 m,mole9) of 4-tetrahydropyranyloxy-2-(6--carbotetrahydropyranyloxy 2-cis-hexenyl)cyclopent-2-en-1-one (Example 9) in 60 ml. of ether at 0-8. The mixture is stir-red at 0 for 1 hour and 25 for 20 hours, diluted with ether, and poured into a stirred mixture of ice and 20 ml. of 37%
hydrochloria acid. The aqueous phase is separated and extrac-; ted with ether. The combined organic phases are washed &UC-cessively with water and brine, dried over magnesium sulfate,~and~concentrated to give an oil.
The crude product is dissolved in 425 ml. of 4:2~
acetic acid-tetrahydrofuran-water, and the resulting solution is heated at 45 for 4 hours. m e solvents are removed in 25 ~ ~vacuo at 20~to~give a mixture of oil and crystals.

-The crude product is purified by partition chroma-tography on a~id-washed silica gel using the conjugate phases from~benzene-methanol-water (15.5:2). The prostadienoic acid is thereby obtained~as an oi}, max. (film) 3300 (hydroxyj, 1735 (cyolopentanone), 1705 (carboxylic acid), and 967 cm~

:
, `~ .
.

Sl;~

(tra_s-ole~in).
EX~MPLE:S 4:2:-:49 ~ ; ~ , The product 9-oxo-ll.a- hydroxy-5-cis,13-trans-pro--stadienoic acids of Table 15 below are obtained by the pro-cedure describe~ in Example 41. In accordance with the pro-cess described therein, the starting triphenylmethoxy sub-stituted l-iodo-trans-l-alkenes listed in Table 15 are treated with butyl lithium providing the corresponding triphenylmeth-oxy substituted trans-l-alkenyl lithium derivative which on treatment with trimethylaluminum furnish the corresponding ...
~lithio trimethyl (triphenylmethoxy substituted trans-l-alken--yl)alanates, which in turn are treated with the 4-oxycyclo--pent-2-en-1-ones listed in the table. The resulting tri-: --phenylmethoxy substituted 9-oxo~ -tetrahydropyranyloxy (or lla-trialkylsilyloxy):-5-cis,13-trans-prostadienoic acid .-.
. .
tetrahydropyranyl ~or trialkylsilyl) ester is hydrolyzed to ~
:the listed products by treatme~t with acetic acid:tetrahydro- : .
. .
-furan:water. . : :

20~

.

. .
.
~ 30 ~ ~

:
~ - 76 - .:
~; ' ' - ~L0~5131 _ .

~ 91 ~ o c~ C ~I s G ~ d N

b X ~ 'I C C~l c C~ ~,~

¦ S ~¦ s ID sS C S X o " X " X

~ ie ~
U~ . . . __ __ . _ _ _ _ , :' ~! ~J
. ~ ~ ~ o ~ , .
.~
:

:~ o~ i._ :~ ~o ~o ~
j_ : ~ ~
a~ O O) a~ . ', . .
. :' .' ~ .
- ; --~
~. ~ ~ ~ ~
E ~ ~

:

~ ' .

5~31 - EXAMP;L~5: 5:0: 58 The product 9-oxo-5-eis,13-trans-prostadienoic acids of Table 16 below are prepared by treatment of the cyclopenten-one methyl esters listed in Table 16 with the appropriate lithio trimethyl(triphenylmethoxysubstituted-l-trans-alkenyl) alanate from the corresponding l-iodo-l-trans-alkene listed in Table 16 followed by di-0-tritylation of the intermediate triphenylmethoxy substituted methyl 9-oxo-5--cis,13-trans- ~ .
prostadienoate followed by saponification of the resulting hydroxy substituted methyl 9-oxo-5 c s,13-trans-prostadienoate.

. ~

, " ' ~; ' ' ' ~.

~' ;`` `

~ ' . ~ ' .

, ' ` ' ~ ~

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

, , ~ . . . :

:l(J~513~L
.
. . ~
u~ o I o ' ~1 U ~ ~1 ~1 ~ ~ ,. ~ .,, ~ V ,, r~
~, ~ ,~, ~ I s~ U~ U~
~.1~) ~! .IJ Il').IJ I ~1 O I U~ I I I r-i t~
rl ~ ~i ~ ~ I
r01r~ O r~
. u~ 1'1 ~n ~ ~ O
~S.~1 I rl 0 rl E~ ~
IJ V ~1 V I U I O
I ~ I O I ~ .C
S-l ~ S
e ~ 0~ ~ 0~ 0 ~
r I ~ ~
I ~ .,1 ,1 ~' ,1 rl ~ ~d ~r O rl Q 51 ri~1~ Q rl V i I V I I O i ~ ~1 0 0 5:) Q (~ Q ~ 1~ ~1 r~ >1 ~ S I V `~ ` U ` ` C~ S
to ~ ~ 1 .,,a~ ~ ~r o ~ ~ o ~ ~ o 0 Y ~'V ~ 0 ~ ~ 0 ~ -V `, Lt~ X ~ X rl X-rl X-~ X-ri X-~ X
l 0 0~ OU 0~ O~ 0~ 0 O ~ V S~ C) :' x ~-~ a ~ ~ ~ ~ ~ ~-'1 o~ o . ~ ~ tn ~ o ~, l ~ ~ S 0: S-H .; O,5 rl ~ O S ~ : .
ci~ ~ 1 1 o I ~ I o I )~ ..
. U~ -rl ~i ~a rt Iri 0 ~i Ir-i 0 r~ 3 ~ .
u I a~ , I ~1 .1 u~I ~ I ~
0~ O:rl0~ 0 ~ 0~ 'O ~ 0~ . .
X U~ X VX ~ X ~1 ~ X ~ax ul ~ . .
O 0 0 0 :10 ~ 0 ~ 0 ~ O S~ 0 0 .,- ,. .
h I S~ I ~Q I ~ I ~ : . .
P~ ~ ~ , a~ I a~ ~. :, ::':'.. ' _ ~ _ ,, :' :
:' ' ' ~1 a) I
D ~ 0: ~ :, '-r-l 0 ~ I r-l0 _1 0 U~ 0 ~i P ~ ~ ~ ~ li H ul: ~ aH ~ 0 rl h rl ~ 0 sl ~ ~ x~ ~ 0 ~ ~ 4 rl 4 . tJ)~ 1 ~ E3 u o ~ 3 V .
I O I ~ o ~r ~ ~ I ~, ~ 1 51 o ~, . , ' ~ ~ ~ o~ ~ ~a o I ~ O ~ ,~o~ x ~
S~,5 0 0 ~ O .5 1 ' O ~ 0 0 .~ ,C
a~ ~ .~ ~ nl . 1 0 I ~ ~ I ~. v u~ ~ ~ ~i ~3 0 ~ ~ ~ . ~ .
~ ~ , ~ ~ ' ~ ; 0 ~ ~ ~ ~
,a :~
~ ~ ~ ~ ~, ~ ~ 0 ~ ~ ~ ~ .
r-l ~ . .;
: : U~ , , , :X: : ,: : : :
: ~ : :: :

\~
_ . 79 i :
~ :

10~5131 ~ o'`l ~1 o .~ :~
-h ~ N ~rl .

o j o R
N~

~ OI ~

A ~ ~I X l~il ::~ h O, o ~ p~
.~ ~ ~:0 , ~_ I ~ ~ N N .,;
u~ ~ ~
~3 ~ i ~ ~, 1 o 3 3 h S O a~ ~ ~ 1 I ~) ~ N N
, C'~ ~ ....
. . ~,Q "~' '' ' :' ~'~ : .

j i~ ~ ~ ;~
h ~ .
~ : . .
. ,~
: ~ ~ a~ ~ :
:: . .1 ;~, . , :1:
~ ' ''"'', :~ ' ' ~73a~ ~ :

;,' ~(~45~1l31 Exam~le 59 Preparation of 9-oxo~ hydroxy-5-cis,13-trans-prostadienoic acid ~
. .
A solution of 7.16 g. (6s m~moles) of l-octyne in 12 ml. of benzene is treated with 52 ml. of 1.2 M diisobutylalu-minum hydride in hexane, and the solution is heated at 50C.
for 2 hours. The solution is cooled to 2~C. and treated dur- , ing 10 minutes with 28.5 ml. of 2.1 M methyl lithium in ether.
The resulting soIution is stirred at ambient temperature for 20 minutes, cooled to 5c., and treated with a solution of 20.1 g. (50 ~moles) of crude 4-tetrahydropyranyloxy-2-(6-carbotetrahydropyranyl-2~cis-hexenyl)cyclopent-2-en-one (Ex-ample~9;) in ~ ml. of ether during 10 minutes. The mixture .
, isthen~stirred at ambient temperature for 20 hours, diluted 15~ ; to ~50 ml. with ether, and poured into a stirred mixture of 400 g. of ice and 90 ml.~of 4NHCl. The organic phase is separated, and the aqueous phase is extracted with additional .
ether. The organic phase is extracted with additional ether.
The organic extract is washed successively with ice-cold i ~:
hydrochloric acid, water, and saturated sodium chloride sol-ution. The extract is dried~;over magnesium sulfate and con-~
~;centrated at reduced pressure to gi~e an oil, max. = 1735 (carbonyl~groups), 1035 (tetrahydropyranyloxy groups), and 965 cm ~(trans vinyl~group~). A solution of this crude oil, 25~ crùde tetrahydropyran-2-yl 11a-tetrahydropyranyloxy-9-oxo-5-cis-13-tra~9-prostadlenoate~in one liter of glacial acid- ~;

tetrahydrofuran-water (4:2:1) is stirred at 45C. for 3.5 hours.; The~cooled solutlon is treated with a solution pre-pared~from one~ ter of~water~and S00 ml. of saturated sodium 30 ~ ch10ride~901ution and~extraoted with ether. The extract is 1~5~31 washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil,~ max. = 1740 (ketone caronyl group), 1710 (acid carbonyl group), and 965 cm~l (trans vinyl group).
!~ =, .
Treatment of the 4-oxycyclopentenones listed in Table 17 below with the lithio methyldiidobutyl(l-trans- -alkenyl)alanates, prepared from the l-alkynes listed in Table 17, diisobutylaluminum hydride and methyl lithium, ~ol-- lowed by deblocking the lla-hydroxy and carboxylate groups all by the procedures described in Example 59 above, furnish-es the product 9-oxo~ - hydroxy-5-cls-13-trans-prostadienoic acids of the table.
.:, .

, '"', '.
... .

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

.

1()4~
~ ~ -rl ~ 0~q ~rlO
0 C) rl ~ r~ O~
o O ~ C)0 0t~Q, I .
~rl ~ a) o~ vu7 O
1 1 ~ 0~7 r a) r~ ~ ~ rlr l Os:~
,1 .,, ~ ~
~ o ~ 0 IdU~ OrlI
~ (1~u~ O ~~ .,1 ~ t~7 IJ U ~ Q~ ,7 y ~ ~ ~1 O ~ ILl) ~ ~ u.7 ~1 O I u~ Ql I U~ U~ rl Ql ~ ~ s~ l ~ o ~ u ~ r 0 ~ ~ r3 ~1 ~ u7 i ~ ~ U~ U~ Sl I r7 ~ 1~ ~ ,~ O
0 7 r I 1 1 0 O rl 7 ~ tQ r l t~
r l ~ u~ rl ~ ~ I r1 1 ~ I rl c ~ u~ a~ o u) ¦ u~ c~ , rl r~1 r l u~ t~l ~ ~ I ~ I l-7 c C.? I 0 17 1 -I oo u~ I~ a~
I ~1 I ~1 U7 r l ~rl ~ r-l I: ~ ~ ~ o o 7 ~ r l ~ ~-~7 ,~ rl ~ 7 ~7 C r l ~) ~ rl r ',~ , ¦ ~3 0 S ~: ~0 ~ .
U7 I r~l N r-l ~ N U7 r l i r I I I
i oX ~ X ~oC o aJ ~OC O X ~
I ~ 1 C) O ~ ~1 ~ ~ ~ rl ~ ~ ~ ~d X ~ O
~ ~ S O
t~ Ci~ ~ S rl ~ O
rl rl rl r-l r~l rl ~ rl rl rl ~
~ r~l rl rl _I ~1 Id rl rl rl 0 1~1 O I I I I I ~ I I I rl P3 ~ X~ X ~ X r~s X X o X x X ~
~i Q O O rl O rl O O S-l O O O ~
E l ~1 I I c~ 1 1 0 ~ a~ ~ a I

_. ` . .
__ . .. ~ .
. ~. ~ '.',",, ;~i ~ ~ I X~
r~ rl 0 : ! . C~ ; ~ ~
rl rl rl 0 rl 7 0 ~ v r l ~q ~ 1 0 ~
: ~ ~ ~ ~ S: ~ ~
0 ~ ~ 7 c) ~ 3 r I r I r I oL7 u7 r/ o 1 u7 ~ ~ 0 ~ ~ .
rl~ a~ rl ~
` ~ ~ sO ~ ~
'~ ~ ,~ X O~ ~ ~' ~q ~ ~40 ., ~: : : 0 : ~ : ~ .
~ C~ r7; ~r u7 ~ . .
' , .
._ :. ~
.
: . -.
~. ` : ' -- ~ - -u ~ I ~ C l c Cl ~ ~u ~ ~ c ~ o ~ P ~ ~ a a ~ ~

Irlt N C: ' ~, .,~, ~ C ~ 0~ '-1 ~ O ~

~¦ ¦ x ¦ x # x x # ~ ~ D ~ ¦ C ~ ~ ~
9 ~ I a ~ P ~ P~~a ~ a ~ O O

: - ~ x ~ ".... ..

a !~ c C ~ !~ 8 2~ o :~ ~ . ~ ~ ~ ~ , .
: x~ ': :: I ~
: c~ ~ : 3 ~ ô _ ~ : ~
, :.~ u: ~ . ,.

~ : _ . . ... _ .. _ . . .
~ ~a) ~ ~
~, ~
: : ~ ~ ~ o ~ ~ , ", .: . .
X ~ ,... : :.
~ ~ ~ ~ . = ~ ....
......
. . .
`3 - `

, .
. .

~' , , .

1(~45~3:1 .
~a ~ o t~ ~ ` h h ¦ ~ I U ~
O ~ I ~ h ~ ~ ~ hl _ O
~ U~ ~ ~ ~ ~ ~ t) .
0: .t) ~ .h ~ S-I u~ I ~. 0 t) ~: I~ .tal ~ o J~ I 'I x I
U O ~ ~ ~
~: ~ Q l O l ,~ 1 ~ , . .
~ ~ $1 ~ ol ~. ~ l l .~. ~ ~ 0 ~ 0 ~1 ~
~ o ~ l l ~ ~ ~:
~ ~ ~ l ~-~ ~ ~ l l 0 ~

`I' 0 . ~, ~ ~ ~ ~
u ~ -o ~ ~ ~
U~ ~ er ~ ~ r _ 1 I ~ I I rl I ~ I rl 1' 1 ~ I
X~ oX ~ O 0~ X~ o~d X oX ~ O ~' ~ X
s~ s~ ~ o o ~ ~
.U ~ O ~O ~O ~ s.u ~ ~ 8 ~ ~ , 0 ~ s U s o ~ o ~ ~
~ ~ ~ ~ ~ ~ U ~ ~ ~ ....
~:t. I ~ I ~ I O I ~ O O
.~X' X U3 0 ~ X O X ~1 X ~Q~C 0 X In X m ~ .
O l ~0 ~0 ~ 0 ~ ~0 1 ~ 1 S~ Ll ~
U a~, . ~ S~ ~
. . , , , , 1 ~0 ~0 _~ ~ . ~ I ~0 0 ~ ~v~ ~ ~ ag' V~ og~ ~ A ~1:
.~ ~ ~. O C) O 0 1 ~ U ~ ~ ~ _ _ 1~ ~ ~ ~ o ~ Y g ~ I I . , U~ ~ I U I ~I CD I ~-~ I
: ~ ~ X ::';
, ~ ~ .,~
X0, ;; ~ : ~

:: ~ 0 ~ ~ ~ ~ O
C~ R. . q~ ~ t~- ~ . tr rC ~ ~S ~ 1 : ~ : ~0, ~ _ _ ~ 0 ,~, '. .

. ~ ~ ~ ~ ~

" : ~ 11 i ll : ~ : : :: : : :: i : : :

: :.
: ~: : : :: : ~
: :

~45~3~

U

In ~ ~1 0 0 _1 ~ ~ I
~¦ ~ 'P ,1 r~
P ~ N in '~ N N ~1 ~ ~ ~ " "

X ~ U ~ td I ' , ."
~1 ~1 U ~ o~1 V 5-1 t) O
~ .c~ ~ ~ s ~ ~ i .. ~.~

e x O o x o x o X r~ X e X ~ I X hO h S
c) o~ o~ I S.l . ., , r~ _ . - -~. . .. 0 ~ 5 5 .~ .. ... . . o ` ;: X ~ ~: - ~ :

: ~ : : ,e, ~ ~ : ~ ~ ~ ~ _ ~ o ': ~ ~ ~'; : 5~
~ ; ~ I :
: ~ ~ , ~ . , - ~
: ~ ~ a, ~ ~ ~ 11 ~
X ~ rl -. ~
__ ~ ' ;"' ' :.

:
:
8 5~

: ~ . , ' ' :' ': , ~{~4~i13~

EXAMPLE l00 Preparation of 9~ ,16-trihydr;oxy-5-cis,L3-trans-prostadie-noic acid To a stirred solution of 459 mg. of 9-oxo-11~,16--dihyroxy-5-cis,13-trans-prostadienoic acid (Example 41) in 4.0 ml. of tetrahydrofuran is added 5.2 ml. of a 0.65M solu-tion of lithium perhydro-9b-boraphenalyl hydride in tetra-hydrofuran at -78~C. under nitrogen. The solution is stir-red at -78C~ for 45 minutes and at ambient temperatures for ~i 15 minutes. The solution is diluted with 10 ml. of water an* extracted with ether. The extract is back-extracted with sodium bicarbonate solution. The combined aqueous phases are acidified with 4N hydrochloric acid, saturated with sod-ium chloride, and extracted with ether. The extract is L5 washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by thin layer chromatography on silica gel to give a color-less oil, max. = 3310 (hydroxyl groups), 1705 (acid carbon-yl group), and;970 cm 1 (trans-vinyl group).
ExAMæLEs 101 - 108 .. . . _ , :
Reduction of the 9-oxo derivative listed in Table 18~below with lithium perhydro-9~-boraphenalyl hydride by the method~described in Example 100 furnishes the product ~9a-hydroxy-5-cis,13-trans-prostadienoic acids of the tabls. -~-..
~ 30 ~ ~
: : .
&6 - i -: ' : ' .:

.... . Starting ~r-oxo -5-cis,13-*rans- Product -prostadienoic 9a-hydroxy-5-cis,13- ::
acid of -trans-prostaaI~noic . Example Example acid : :
_ ., ~ : .
. .
101 4 2 9a ,11 a ,1 6-trihydroxy-20--methyl-5-cis,13-trans- -. -prostadienoic acid ..... .....
102 43 9a,11a,16~trihydroxy-20- .::
-ethyl-5-cis,13-trans- :.
prostadienoic ac~~~~ ;.
103 44 9a,11a,16-trihydroxy-20--nor-5-cis,13-trans-pro--stadienoic acid . :.
104 45 9a,11a~16-trihydroxy-19, . -0 dinor-5-cis,13-trans- : .
-prostadienoic aci~ .
105 46 9a, lla ,16-trihydroxy-19--methyl-5-cis,13-trans- . .
-prostadienoic acid :
106 47 sa,ll,l6-trihydroxy-17- ..
. -ethyl-20-nor-5-cis,13- . . .
: -trans-prostadienolc acid 107 48 9a~ 11 a, 16-trihydroxy-20- . .:
-methyl-5-cis,13-trans, .. ;
. : : 18-c -pro~trienolc acid 108 49 9a,11a,16-trihydroxy-18, .:~ ..... .
19,20-trinor-5-cis,13-tr:ans- .
: . -prostadienoic acid '' ' . . . .. .. . .. ~ : ., . .:
:
.

., ' :,.
:: :::., . ;.
.:
, : , ' .
' :
, '-`

~04S13~

E~A~PLE :10 9 Pr;epax~ti.on::of::9:-.oxo-16-hydro~:y-5-.cis-:10:,13-t'rans~rostatri-enoic acid :
A solution of 1.52 g. ~A..3mmoles) of 9-oxo-lla,16--dihyroxy-5-cis,13-trans-prost:adienoic acid (Example 41) in 80 ml. of O.SNHCl in 1:1 THF-~20 is allowed to stand at room temperature under nitrogen for 67 hours. The solution is treated with brine and extracted with ether. The extract is washed with brine and dried over magnesium sulfate. The re- - ..
sidue remaining after evaporation of the solvent is purified by partition chromatography on Celite~ to give an oil,~ max (film) 1700 (ketone and acld carbonyl groups) ! 1580 (conju-gated olefin), and 967 cm 1 (trans-olefin).
: ~XAMPLES 11 o 1 1?
Treatment of the 9-oxo-lla-hydroxy-5-cis,13-trans--.'~.
: -prostadienoic acids listed in Table 19 below with dilute -:
. .:: .
acid in accordance with the method described in Example 109 furnishes the product 9-oxo-5-cis,10,13-trans-prostatrienoic' :~.
aclds of thè table. ~ : ~ .~.. '' : ~

, ~ `:; 25-: : :~: -: ~
. -- :

::
: . .

S~3~

....... .
. ....... __ . ~ _ . . : .:
Starting 9-oxo-~ ,hydroxy-5--Cl: 13-trans Product 9-oxo-5-cis,---prostadienoic 10,13-trans-pros~~ri~ .
Example acid of Example enoic acid ':
. - . ._ _ ~ . ..

110 42 9-oxo-16-hydroxy-20- ' -methyl-5-cis,10,13--trans-prostatrienoic . ~''.
a~ " :
111 43 9-oxo-16-hydroxy-20--ethyl-S-cis,10,13-tr:ans- . ::
-prostatrienoic-acid ' 112 44 9-oxo-16-hydroxy-20-nor- ': ':
: -5-cis,10,13-tran:s-pro-: -st~~ienoic ~a~
113 45 9-oxo-16-hydroxy-19,20- ..: .
-dinor-5-cis,10,13-trans- . .'' .
. -prostatrienoic acid''~~'''~' '' ' 114 46 9-oxo-16-hydroxy-19-methyl- : ~ ' -5-cis,10,13-*rans-prosta- '.. : ::
trienoic acid ~ :
115 47 9-oxo-16-hydroxy-17-ethyl- ~ .
-20-nor-5-cis,-10,13-trans-: :~ ~ -prostatrienoic acid ~ ~:
. .
:- ~ 116 ~ 48 9-oxo-16 hydroxy-20-methyl- ::-' :~
~ ~ ~: : -5-cis,10,13-tra~s_ 18-ris-: ~ : ~ : -pr~Fatetraenoic''acid :, ~ ~ ~ . :, ,' .
: 117 49 ~ 9:-oxo-16-hydroxy-18,19,- .: .
: : : : 20-trinor-5-cis,10,13-tr`ans-:: ~ ~: prostatrienolc acid : ~ : .
: .... _ . _ ; 8q-. ~ ` -:

1()45~31~
EX~PLE 11 8 Preparation of 9a/~ l6-trihydroxy-5-cis~l3-trans-prostadi ~ enoic;~a~
:
To a stirred~ ice cold solution of 355 mg. 9-oxo--11~,16-dihydroxy-9-oxo-5-cis,13-tr -prostadienoic acid 5 tExample 41) in 50 ml. o~ ethanol is added 409 mg. of sodium borohydride in small portions during 1 minute. Th~ mixture is stirred at 0C. for 5 minutes and at ambient temperature for 1.5 hour. The bulk of the ethanol is evaporated at room temperature, and the residue is tr~ated with ether followed 10by dilute hydrochloric acid while cooling in an ice bath.
The organic phase is separated and washed with water and saturated sodium chloride~solution. The solution is dried -~
over maqnesium sulfate and concentrated. The residue is -purified by thin layer chromatography on silica gel to give 15oil, which is a mixture of 9a- and 9D-hydrox~r derivatives, max. 3310 (hydroxyl groups), 1705 (acid carbonyl group), ~and 970 cm~l (trans vinyl group)~ ~ ;

20 ~
:
. .:

. :- : : ~ :

, 30 ~

~0~5~3~l Treatment of ~he prostadienoic acids listed in Table 21 below with the indicated diazoalkane in the follow-ing manner provides the product prostadienoate esters of the table.
An ethereal solution containing a molar excess of diazoalkane is added to a solution of prostadienoic acid in ether (or acetone). After two to four hours the solution is '.
carefully evaporated under vacuum and the residual prostadie- .
noate ester is purified in the usual way by chromatography .:
on silica gel.

.
,' '.. ,'' .

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

:: : :
,.

~: : ~ : : : .
~ 25 ::~

:: : ~ :
:

: ~ : .
:
, ~O~S13~
, ~ ~_ ~
0 ~ 0 ,,.,, 0 .

0 0' ~ ~ ~ ~ O ~ ~
.,, .,, ,, ,, ~ 0 ,, ~ 0 0 .,, ~ ,, ~ ~q 0 ,, ,,'~ (d ~ ~ ~ ~ 5 s~
o o o o ~ ~ o ~ o ,~ ~ ~ ~
o S~ S~ ~ q O O . -o ~ ¦ L ¦ ~¦ ~ ¦ ~ 01 L ¦ ~ ¦ @¦ @ ¦
~ ~ ~ ~ ~ ~ I ~ I ~ I s~ ~ ~
o~ ~ ul ul~.ul ~ U~ OI 0 '~ O O ~
~ , ., , o ~ , ~ , , o ~ ~ ...
K K X o X X X o " o :~, ¦ u I u I ~
~ .~ ,X X~ X~
nt . ' ~4 ~ ~ I J,~ i 1 0 1 ~ : ' ~ S' I I
,- ~ r ~ 1 .. '. ,- '.
~ XO'XOXX~ Xo -~
ii~ a~ a~ h ~ : -:
-0 ~ ~ ~ ~ , : E3 Q~
_ ~ ' :
~ ~ ~ a = ~

N ~ N N N N; N N N N N N N N N
~1 rl ~ rl I ~ ~ : '~
0 U: 0 ~ - :"' ' ., ': ~ ~ : : ~ ~ ~ ,.
,: ~ tJ~-rl` ~ ~ ' ;
~o. ~ --~ r-~ O~ O O O N ~n o o ~:o : ~ '`

: :: : : :
~, 0: _ ~ . " , .
~ l N N N ~ ~ t'~ l N N ~ ~1 : . .
---~ ' a- -.:
..

~04S~l3~

Examp:Le 132 Preparat;ion of; 2 (6-carbo-~-butoxyhexyl)cycl~ent-2-en-~-one A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent--2-en-1-one [Bagli e~ al., Tetrahedron Letters, No. 5, 465 ~, (1966)] in 1400 ml. of n-butanol containing 2.7 g. of p tolu--enesulfonic acid monohydrate is allowed to stand at room temperature in a stoppered flask for about 24 hours. The sol-ution is taken to dryness. The residue is taken up in ether and the ethereal solution is washed several times with saline solution, dried with anhydrous magnesium sulfate, and taken to dryness to afford the subject butyl ester.
Examples 133-135 , ,,.",.~,..................... . .
Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure of Example L32 with the appropriate alcohol affords the esters of the following table.

Exah~pIe ~
133 1 propanol 2-(6-carboisopropoxy~exyl)cyclopent-~ -2-en-1 one 134~ methanol 2-(6-carbomethoxyhexyl)cyclopent-2--en-l-one 135 ~l-hydroxy- 2-(6-carbo-n-decyloxyhexyl)cyclo-pent-2-en-1-one ' . ~; ~ ~ ........................... ' .

:` : :: : : ~
Preparation of 4-bromo-2(6_carboxyhexyl)cyclopent 2-en-1-one-~ ~ A stlrred mixture of 35.9 g. (0.171 mole) of 2-:
~- ~ (6-carboxyhexyl)cyclopent-2-en~l-one ~Bagli et al, Tetrahedron ~: :
Letters, No. S, 465 (1966)], 35.0 g. (0.197 mole) of N~bromo--sucainimide, and 600 ml. of aarbon tetrachloride is refluxed for 35 minutes. ~The mixture i~ cooled to 5C. and filtered.
: , The filtrate is washed with cold water, dried over magnesium ~ ~3 ;', 104.~31 ~ MeOH
sulfate, and taken to dryness to give an oil, r max. = 225 m~
(8850); ~ max. = 1705 (carbonyl groups) and 1625 cm (olefin group).
Examples 137-142 In the manner of the preceding Example (136) the various cyclopentenones of Table 23, which follows, are con-vertqd to the corresponding 4-bromo derivatives.

':
', ' ' `

:

: 20; ~

~ - :

~ 25~ ~

9 :Y - ~

~ 30 ::
~;:: ~ ........ ..

, TABLE 23 :'.

. ........ , .
starting Example Cyclopentenone Product 4-Bromocyclopentenones .
. _ . ~.. . ,, "' ', 137 2-(6-carbethoxy- 4-bromo-2-(6-carbethoxyoctyl)-octyl)cyclopent- -cyclopent-2-en-1-one : :
-2-en-1-one -: -138 132 4-bromo-2-(6-carbo-n-butoxyhex--yL)-cyclopent-2-en-1-one :~
139 133 4-bromo-2-(6-carbo-isopropoxy-hexyl)-cyclopent-2-en-1-one : ~
140 135 4-bromo-2-(6-carbo-n-decyloxy- :.:
hexyl)cyclopent-2-en-1-one 141 2-(6-carbethoxy 4-bromo-2-(6-carbethoxyhexyl)-hexyl)-cyclopent- -cyclopent-2-en-1-one : -2-en-1-one 142 2-(6-carbomethoxy- 4-bromo-2-(~-carbomethoxyhex-hexyl)-cyclopent -yl)-cyclopent-2-en-1-one .' : -2-en-1-one .
., ~ ., :

~':.

~, : : .

: :

9 5_ ---- . :

. .
., L()4S~31 Example 143 Preparation of 4-acetoxy-2-(6-carbethoxyhexyl)cyclopent-2-en--l-one A mixture of 51.6 g, (0.137 mole) o~ crude 4-bromo--2-(6-carbethoxyhexyl)cyclopent: 2-en-1-one, 27 g. (0.162 mole) of silver acetate, and 200 ml. o~ glacial acetic acid is stir-red at reflux for 4.5 hours. The mixture is cooled, and sol-ids are removed by filtration. The filtrate is concentrated and extracted with hot hexane. The extract is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concen-trated to give an oil. The crude product is distilled at re-duced pressure to give a liquid, b.p. 152-163C. (0.01 mm);
MeOH
/ max. = 223m~ (10700); ~ max. = 1745 (ester carbonyl groups), 1725 (ketone carbonyl groups), and 1235 cm (ace- ;
toxy group).
~ ' ' Preparation of 4-hydroxy-2-(6-carboxyhexyl)c~clopent-2-en-1-one To a stirred solution of 6.91 g.(So mmoles) of potas-sium carbonate in 1400 ml. of methanol and 1400 ml. of water . .
. .
containing 100 mg. of hydroquinone is added 14.8 g. (50m~

-moles) o~ ~-acetoxy-2-(6-carbethoxyhexyl)-cyclopent-2-en-1-one . ~ . .
; ~ (Example 143) during one minute at room temperature under ni-~trogen. The solution is stirred for 90 minutes and at this ~ stage it contains 4-hydroxy-2-(6-carbethoxyhexyl)~cyclopent-2-en-I-one. It is then treated with 23.6 g.(75 ~moles) of barium hydroxide octahydrate duxing one minute. The mixture ~is stirred for 60 minutes and then is concentrated at reduced ~pressure~to a volume of 1800 ml. during one hour. The solu 30 tion is diluted with 300 ml. of water, saturated with sodium ;~

~, .

, ,.
:.
: . . .

~s~

chloride, and stirred with 400 ml. of ether whi~e 70 ml. of 4N hydrochloric acid is added. The aqueous phase is extracted with additional ether, and the combined organic phases are washed with saturated sodium chlordie solution. The extract is dried over magnesium sulfate. The crude product obtained after evaporation of the solvents is puri~ied by chromatography ~ MeOH
on silica gel to give an oil,~ max. = 223 m~ (7360;~ max.
= 3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm 1 (olefin group).
Example 145 Preparation of 2-(6-carboxyhexyl)-4-hx~roxy-cycl~ ent-?-en-l-one To a stirred solution of 10.6 ~. (ca. 34 m moies) of crude 4-bromo-2-(6-carboxyhexyl~cyclopent-2-en-I-one (Example 136) in 100 ml. of acetone and 65 ml. o~ water is added 8.80 g. (45.2 m mo`les) of silver fluoborate during 2 minutes. The temperatuxe is maintained at 25-30C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions.
,~ .
~ 20 The basic solutions is reaoidified with dilute hydrochIoric .:
-~ ~ aoid, saturated with sodium ohloride, and extracted with ether.

~The extract~is washed with water and saturated sodium chlor-ide~ solution, dried over magnesium sulfate, and concentrated.

~The~crude produot is purified by partition chromatography on 25 Celite~ to;give an oil with the properties described in Ex-:
ample 6Z4.

ExamE~les 146-151 By the procedure of~the preceding Example, the var--~ious 4-bromocyolopentenones of the following Table 24 are sol-~ volyzed Ln~acetone-water~in the presence of silver fluoborate .

~ 4Sl3~
to provide the 4-~ydroxycyclopentenones of the Table.

_ Star'ti-ng ' , _ _ _ '' cyclopentenones Product Exampleof Example 4-~hydroxycyclopente-2-en-ones 146 141 4-hydroxy-2-(6-carbethoxyhexyl)-cyclopent-2-en-1-one 147 142 4-hydroxy-2(6-carbomethoxyhexy)-cyclopent-2-en-1-one 148 137' 4-hydroxy-2-(6-carbethoxyoctyl)-cyclopent-2-en-1-one 149 13~ 4-hydroxy-2-(6-carbo n-butoxy-hexyl~cyclopenti2-en-l-one 150 139 4 hydroxy-2-(6-carbo-isopropoxy- , , , hexyl)cyclopent-2-en-1-one , 151 140 ; 4-hydroxy-2-(6-carbo-n-decyloxy-hexyl)cyclopent-2-en-1-one . . i . _ _ . . :. -.
.. .
Example 152 : .
Preparation of 4-tetrahydropyranyloxy-2-(6-tetrahydropyranyL- ,-carbo~vhexvl-)avclo~ent~2-en-1-one , : .-',To a stirred solution of 5.59 g. (24.6 m moles of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 145)~ , -20and 20.7 g. t246~m m~les)of dihydropyran in 100 ml. of methyl-.
ene chloride at 20C. is added 47 mg. (0.246 m,moles) of p-tolu- ,, ii ~-enesulfonic acid monohydrate in one portion. The tempera-ture~ maintained at 20-25C. by cooling and is stirred for one hour at that temperature. The solution is diluted with 25200 ml.~of ether and~ poured into a mixture of 40 ml. of sat- ~ ' urated'sodium~bicarbonate solution, 40 ml. of saturated'sod- '' ,~; ' -; ~ ium chloride solution and 80 ml. of~water. The phases are '' separated, and the~ aqueous phase is extracted with additional ~' '' ether. The total extract~ lS washed successively with water and ~, ;~saturated sodium~chloride 501ution7 dried over potassium car~

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

3:L :
bonate, and freed of volatile matter by concentration at re-~ MeOH
duced pressure to give an oil,/ max. = 223 m~ (9500);
~ max. 1730 (~ster carbonyl group), 1705 (ketone carbonyl group), and 1030 cm (tetrahyclropyranyloxy groups).
E amples 153-155 By the procedure of Example 152, the various 4-hydroxycyclopentenones of ~able 25, which follows, are conver-ted to the tetrahydropyranyl 4-tetrahydropyranyl-oxycyclopen--tenone esters of the table.

_ ~ - ~ ., Starting 4-hydroxycyclo- Product Tetrahydropyran-2'-yl 4-pentenone ~of tetrahydropyran-2'-yl-oxycyclopent ExampleExample~ -2-en-1-ones '~
_ _ _ _ . .
153 146 4-tetrahydropyran-2'-yloxy-2-(4-carbotetrahydropyran-2'-yloxybutyl) cyclopent-2-en-1-one i~ 154 147 4-tetrahydropyran-2'-yloxy-2-(3-carbotetrahydropyran 2'-yloxypropy~
cyclopent-2-en-1-one 155~ (i) 4-tetrahydropyran-2'-yloxy-2-(6-carbotetrahydropyran-2'-yloxyoctyl) ~ cyclopent-2-en-1-one , __ .. . -- - - :
;) = 4-hydroxy-2-~6-carboxyoCtyl)lcyclopent-Z-en-l-one Example 156 ~' PreparatiOn of~4-tetrahydropyranyloxy-2-(6-carbethoxy-hexyl) cyclopent-2-en-l-one 25- ~ i To a stirred solution of 674 mg~ (2.64 m m~les)of 4-~hydroxy 2-(6-carbethoxyhexyl)cyolopent-2-en-1-one (Example 146) and~2~22 g. (?6.4 ~ moles)of dihydropyran in 2.6 ml. of ;methylene chlorlde;is added 5.0 mg. (0~026~ mol~sj of p-tolu-~-enesulfonic acid monohydrate~ After stirring for 20 minutes at room temperature the solution is diluted with ether and poured into saturated sodium chlorlde solution containing a :: :
~ 9 ~ _ ` 1S~4S~l3~
little sodium bicarbonate. The organic phase is separated and washed with saturated sodium chlorid~ solution. The ex-tract is dried over magnesium sulfate, and volatile matter is ~ MeOH
evaporated at reduced pressure to give an oil,~ max. = 224 m~ (7950); ~ max. = 1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm (tetrahydropyranyloxy group).
Examples 157-160 In the manner of Example 156 the alkyl 4-hydroxycyclo--pentenone esters of Table 26, which follows, are converted to the corresponding 4-tetrahydropyranyloxy alkyl esters of the table.

:
_ , ~. ~ -Starting 4-hydro--xycyclopentenone Product 4-tetrahydropyran-2'- -Example E:s`*ers of Example yloxy-cyclopent-2-en-1-one OE
. ~ . _.... _ . -~ -. . _ `'i'"
157 147 4-tetrahydropyran-2'yloxy-2--(S-carbomethoxyhexyl)cyclo--pent-2-en l-one 158 149 4-tetrahydropyran-2'-yloxy-2-(6-carbo-n-butoxyhexyl)cyclo-pent-2-en-I one ~
159 150 4-tetrahydropyran-2'-yloxy-2- - ;
-(6-carbo-isopropxyhexyl)cyclo-pent-2-en-1-one 160 151 4-tetrahydropyran-21-yloxy-2--(6-carbo-n-decyloxyhexyl)cy- ~ --clopent-2-en-1-one ~:: : - ... .. ~ .. . ~ ., .
~ Exam~le 161 A 0.05 M solution of~crude tetrahydropyran-2-yl 9-oxy~ tetrahydropyranyloxy-20-triphenylmethoxy-8-13-trans--pro tenoate in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 4S for 7 hours. The solution is diluted with :~ , ... ..
- i Ot~
' '::
'- ' ,~ .
. ' ~(~4~3~ ~
aqueous sodium chloride solution and extracted with ether.
The extract is washed with water and concentrated using toluene for azeotropic removal of aqueous acetic acid. The residue is purified by column chromato~raphy on silica gel to give an oil, ~ max., 1735 (ketone carbonyl group), 1710 (acid car-bonyl group), and 967 cm~l (trans-vinyl group).
Examples 162-170 Conjugate addition of the alanates obtained by treat-ment of the triphenylmethoxy (trityloxy)-l-alkyne (indicated in the following table) with dii'sobutylaluminum hydride fol-lowed by methyl lithium, to the cyclopentenones of the table followed by de-O-tritylation of the intermediate triphenyl--methoxyprostenoates according to the method of Example 161 is productive of the prostenoic acids and esters of the table.
Those compounds isolated and identified in the table as prostenoic acids are prepared via the corresponding tetra-hydropyxan-2-yl esters and these compounds bearing free hydroxy functions at the lla-position or as part of an ll~ J-hydro--xyalkoxy) moiety are prepared via the corresponding tetra-hydropyran-2-yl esthers~ Tbe hydroxy function in the ~-side chain (that portion of the molecule deriving from the tri phçnylmethoxy-l-alkynej of all compounds in the table are ini-tially present in the molecule as the corresponding triphenyl-methyl ethers. During the acetic acid treatment (de O-trityl-.
~ -ation step) the txiphenylmethyl ethex as well as the tetra-hydropyran-2-yl ethers and esters functions are hydrolyzed to provide the corresponding free hydroxy` and carboxylic acid groups of the compounds listed in the table.

10~5~31 _, __ .._ ,~ _ .. , . . _ . .
o , o s~ o ' o ", O ~ ~ I Ql I i 5~ h o ~:: ~ O U~ ~ ~Q ~ U~
ta O S~ ~ I ~ ~ 0 ~ ~
5-1 h ~ ~1 0 h ~ h ~I h ~ ~ 1 ~ :~ ~
~ ~0 ~ 1 ~ X
1:~ ~ I ~ i O
S~
~1 5-1 O O ~ ~ X :~ ~ ~ ., O ~ ~ ~ ~ X h S Xo :~
~ ~ o 1~ .
,1 ~ a I I I I ~ 5~ 1 ~ :: -X ~ X X~ :
C~ O O O O U) _l ~D X ~D
,1 ~ ~1 1 ~1 0 ~1 ., O ~ ~1 ~-rl ~ I ~ I ~-I i ~ ~ ~ ~ t) ~1 ~ X ~ ~ ~ . ' 0 S ~ ~ ~ ~ X O X ~ X
u~ D V u:~ O h ~ '~ h' j.
O ~1 ~1 -I-rl ~ ~d ~ ~ ~ ~5 ~
. P~ I I ~ a ~ -X X~ ~ 0 X rl O O-rl O ~ O O ~ O ~ . , X h h O h lq h a ,i ,1 ~ x ~
O ~ ~ ~ ~ O ~ ~ 1 0 ~1 ~ -.
1-l ~ ~ ~h ~ I O I 1 0 1 ~3, ~ S O .~ n o x o a ~ o .-~ I l-rl I I I O X O X ~ X .
eq i~ ~ o ~5 ~Q~ ~ o 0 1 0 o 0~1 o o 0 ,.
~ a ~ ~ ~
~1 _i 0 --I,~ ~ ~, t) I I JJ I h I ~q O --I O O O ~ O .:
~ O O ;Q O ~ O ~ ,~ a 1~ ~:1 X ~ X O X l X nl ~ 0 ~ 0~ 0 ~ 0 ~ 0 : : :
N : O O ri O S-l O ~ O h ~ ~ ~ ~~ ~ O ht~ ~1 ~:1 I O I ~I ~1 1 ~ ~ ~0 u~ q ~ 0 ~a : :~ ,.
~1 Pi ~ I H I a I
. ~ , . : :.
: ~ ~ . ' ~ ~ . ~ :,, . .,:
' ~ ~ ~0 : ~ ~ ~ ' ~ 0 .
: 'h a~ . -~ ~ ' - ~ : , : :- '': ' ~ I ~ ~ o .~. er COO O O ~ ~ . ~ .
J~ ~ ~ X ; ~ N ~ N ~ ~ l cn ~
~ ~xo ~ ~ ~ ~ :
~ ~ ~: ~
: ~ ~
: ~ : ~ :
-l o ~ 0 ~l ~ ~ ~ :
: t~ ~:: ~ ~ ~`~ : ~ : N ~
~ o ~ u~ D :
~1 a ~ ~
~j oJ X ; ~: : : : ..... ...

_ _~ :, ;: ~ : ~ . :., :: ~i ~ o ~ ~ X: ~ :' . -~ ~
: : ~ ~
:: : : :
:
:
: : 4t ~ :: :
:~

S~31 Ex~m~les:1:7;1=175 Hydrogenation of the 13-prostenoic acids and esters listed in the table below over a 10% palladium on carbon catalyst is productive of the prostanoic acids and esters of the table.

_ . . ._ __ _ - .
starting 13-prostenoic acid or ester (of Ex-Product Example ampleProstenoic acid or este~ . -_. . ____ :, .
171 162 9-oxo-11~-hydroxy-16-. hydroxy-~prostanoic acid . : .

172 163 9-oxo~ hydroxy-16-. hydroxy-2Q-nor-prostan-. oic~acid ~ `
173 166 Ethyl 9-oxo-lla-hydroxy-: -16-hydroxy-prostanoate ~; 15 174 (k) Butyl 9-oxo-11~-hydroxy-: . -16-hydroxy-prostanoate : 175 168 Decyl 9-oxo-11~-hydroxy-: ~ ~ ~ ~ -16-hydroxy-prostanoate ~

(k) Y Ethyl 9-oxo~ -hydroxy-7-nor-16-hydroxy-20-methyl- :
-13-trans-prostenoate.
Reduction of the:~9-oxo derivative listed in the table below:with lithium:~perhydro-9~-boraphenalyl hydride is : -~productlve of the 9a-hydroxy;derivative of the table, : 30 ~(~4S~31 ~AB:LE 29 _ ,, .
Starting 9-oxo de-Example rivative of Example Product 9a~hydroxy derivative . _ _ _. ... ... __ ~ ",: ; . .
176 162 9a, lla ,16-trihydroxy-13-trans--prostenoic acid 177 163 9a,11a,16-trihydroxy-20-nor-. -13-trans-prostenoic ~cid ~:
178 164 9a,11a,16-trihydroxy-17- ~:.
methyl-19,20-dinor-13-trans-. prostenoic acid 179 165 9àJlla~l6-trihydroxy-l7- eth~ ~ :~
720-dinor-13-trans-pro--stenolc acid ~ :. ...
: 180 166 Ethyl ga,lla,l6-trihydroxy-: -13-trans-prostenoate 181 168 Butyl 9a~ lla ,16-trihydroxy- ; .
-13-trans-prostenoate .~ .
182 170 Decyl 9 a ,11 a,l6-trihydroxy-: . -13-trans-prostenoate ` . . :
183 175 ~ Decyl 9a,11a,16-trihydroxy-. . -prostanoate , _ . ~ - -- Ex:ample 184 . ~.
:20- . Preparation of 20-hydroxy-.9-oxo.-10,.1.3~-.trans.-pros.tadi.enoi.c.. a.c.id~
A:.solution of 355 mg. (l.OO m mn.les) of 1~Y,20-di--hydroxy-9-oxo-13-trans-prostenoic acid (Example 161) in 6.67 ml.~of l.5N hydrochloric acid ànd 13.3 ml. of tetrahydrofuran . . `:
is alIowed to;:stand at room temperature for 70 hours. The .
solution is~treated wlth: saturated sodium chloride solution and extracted with ether. The;extract is washed successively with water and saturated sodium chloride solution and dried : ~ : , . . ! ':
over magnesium~sulfate. The: crude product obtained after ev- .
aporation of the~solvent s purified by chromatography on sili-ca gel~to give:an oil, ~ max. ~- 217 m,u (9500); ~ max = 1700 :~ : '; ` : : '.-,', ':

. .
,.:

S~3~
(acid carbonyl group), 1690 (ketone carbonyl group), 1585 (con-jugated olefin group), and 965 cm (trans vinyl group).
Exa~pleis::185 193 Acid treatment by the procedure described in Example 184 of the ll~-hydroxy-9-oxo derivatives listed in the table below is productive of the ~ 10 derivatives of the table.
T~BLE 30 . . _ . /~
Starting lla- , . -hydroxy-9-oxo- Product deri~ative of 9-oxo-10-prostenoic acids and . Example Exampie esters _ _ . . ~ .
185 (1) 9-oxo-2-phenyl-16-hydroxy-20--ethy].-10,13-trans-prostadienoic acid 186 168 Butyl 9-oxo-16-hydroxy-10,13--tra~s-prostadienoate 187 169 Isopropyl 9-oxo-16-hydroxy-10, : . 13-trans-prostadienoate 188 170 ~Decyl 9-oxo-16-hydroxy-10,13-. -trans-prostadienoate . 189 162 9-oxo-16-hydroxy-10,13-trans-: . . . . -prostadienoic acid - .

190 163 - 9-oxo-16-hydroxy-20-nor-10,13-:~ :: ~ -trans-prostadienoic acid ~191 164 9-oxo-16-hydroxy-17-methyl-19:, : 20-dinor-10,13-trans-prosta-dienoic acid : 192 165 9-oxo-16-hydroxy-17-ethyl-20-: -nor-10,13-trans-prostadienoic :
; 193 171 ~ 9-oxo-16-hydroxy-10 prostenoia ,, :~: ~ ~ :

:; 30 . .
, .

513~
Example 1~94 Preparation of Capsule Formu;lation Ingredie;nt Milligrams per C;a;psule 9-oxo~ ,16-dihyroxy-5-cis--13-trans-prostadienoic acld 5 ' Starch 80 Magensium Stearate 5 The active ingredient, starch and magnesium stearate are blend- ' ed together. The mixture is used to fill hard shell capsules ,' of a suitable size at a fill weight of 90 milligrams per cap~
sule. -' ' Example 195 ~ -Prepara;tion of Tablet Formulation i -In~redientMilIigrams per Tablet ~
9-oxo-lla,16-dihydroxy-5-cis- ^`'''.:'.''''-13-trans-prostadienoic acid 2 , ,,', Lactose 200 ;~
Corn Starch (for mix) 50 Corn Starch (for paste) 50 Magnesium stearate 6 The active lngredient, lactose and corn starch (for mix) are ,-20~ blended toget~ar~ The corn starch ~for paste~ is suspended in water at,a ratiO of 10 grams of corn starch per 80 milli ~ - ~ liters of water and heated with stirring to form a paste. '-,~ ~ Thls paste is then used ~o granulate the mixed powders. The , wet granules are passed through a No. 8 screen and dried at , ~5 ~120F. ~The dry granules are passed through a No. 16 screen. ' ;
The~mlxture is lubricated with magnesium stearate and compres- ,' sed into tablets in a suitable tableting machine, Each tablet ' '~
- . . .. .
~ contalns 2 milligrams of active ingredient.
: : , ... .

,~ . , .: - - - - - -- . .. . . .
b(o-- : ~
, , , ' ', :~

lQ~5~3~
Example 196 ~ Syrup Formulation Ingredient Amount 9-oxo-lla,16-dihydroxy-5-cis-13- 5 mg trans-prostadienoic acid Sorbitol solution (70~ N.F.) 40 ml.
Sodium benzoate 150 mg.
Sucaryl 90 mg.
Saccharin 10 mg.
Red Dye (F.D. & C. No. 2) 10 mg.
Che~ry Flavor 50 mg.
Distilled water qs to 100 ml. ;
The sorbitol solution is added to 40 milli~e~s~r ~f distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.
Other ingredients may replace those listed in the above Eormulation. For ;example, a suspending agent such as ~ bentonite magma, tragacanth, carboxymethylcellulose~ or meth-~ ylcellulose may be used.~ Phosphates, citrates or tartrates may be added~as buffers. Preservatives may include the parabens, sorbic acid and the like and~;other flavors and dyes may be ; used in place of those listed~above.
. . .: .

25~ Example 197 Ingredient 9-oxo~ ,16-dihydroxy-5-cis-13- 0.5 trans-prostadienoic acid Starch ~ ~ ~ 80 Magneslum steara~te ~ 5 . .

. ~ . . ... . . . .. . ........................................................ .
. ' i ,, ', ~ ' ,,; ' `' ' ' , ! , . . .

` 1()4S~3~

The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell cap-sules of a suitable size at a fill weight of 86 milligrams per capsule.
Example 198 Preparation_of Table-t Formul;a;ti~n ~- -In~redient Milli Q ms per let 9-oxo~ ,16-dihydroxy-5-cis-13-trans-prostadienoic acid 0,25 Lactose 200 10 Corn Starch ~for mix) 50 Corn Starch (for paste~ 50 Magnesium stearate 6 The active ingredient, lactose and corn starch (~or mix) are blended together. The corn starch (for paste) i9 suspended in water at a ratio of 10 grams of corn starch per 80 milli-liters of water and heated with stirring to form a paste.
Thls paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120F. The dry granules are ~ passe~- through a No. 16 screen.
The mixture is lubricated with magnesium stearate and compr~ssed into tablets in a suitable tableting machine. Each tablet . ~. .
~ contains 2 milligrams of active ingredient.

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

o :
~ '

Claims (3)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing the optically active enantiomers of the formula:

(I) wherein the moiety is selected from the group consisting of , , and wherein R1 is hydroxy or alkoxy (C1-C10), R4 is H or OH and Z is the moiety -(CH2)6-, , -(CH2)4O-CH2, or (CH2)4-S-CH2, with the proviso that when Z is (CH2)4SCH2 then R4 must be H; C13-C14 is ethylene or trans vinylene with the provlso that when Z is then C13-C14 must be trans vinylene; R2 is hydrogen, methyl or ethyl, R3 is straight chain alkyl (C2-C5) and the mirror images and racemates thereof and when R1 is hydroxy the pharma-ceutically acceptable salts thereof, which comprises reacting a compound of the formula:

(IV) wherein R5, Z, R6, R2, and R3 are as hereinabove defined, to deblock the ether and ester groups with weak acid to glve a compound of the formula:

(V) trans where R4, Z, R1, R2 and R3 are as hereinabove defined, and where required treat-ing the compound of Formula IV or V with dilute mineral acid to give a compound of the formula:

(VI) wherein R1, R2 and R3 are as hereinabove defined and Z' is selected from the group consisting of (CH2)6, CH2, CH=CH(CH2)3 and -(CH2)4OCH2 and where required treating the compound of Formula Vcis with a sterioselective hydride reducing agent to give a compound of the formula (VII) trans wherein R1, R2, R3 and Z are as hereinabove defined and where required treating a compound of Formula V with a hydride reagent to give a compound of the formula:

(VIII) wherein R1, R2, R3 and Z are as hereinabove defined, and where required hydro-genating the double bond to give a compound of the formula:

(IX) wherein R1, R2 and R3 are as hereinabove defined, Z" is selected from the group consisting of (CH2)6 and (CH2)4-O-CH2 and the moicty is selected from the group consisting of:

, and .

2. A process for preparing the optically active enan-tiomers of the formula:

I

wherein the moiety ? is selected from the group consisting of , , and wherein R1 is hydroxy or alkoxy (C1-C10), R4 is H or OH and Z
is the moiety -(CH2)6-, , -(CH2)40-CH2, or (CH2)4-S-CH2, with the proviso that when Z is (CH2)4SCH2 then R4 must be H; C13-C14 is ethylene or trans vinylene with the proviso that when Z is then C13-C14 must be trans vinylene;
R2 is hydrogen, methyl or ethyl, R3 is straight chain alkyl (C2-C5) and the mirror images and racemates thereof and when R1 is hydroxy the pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula:

II

wherein Z is as previously hereinabove defined with the proviso that when Z is (CH2)4SCH2 then R5 must be hydrogen, R5 is hy-drogen or tetrahydropyranyloxy and R6 is tetrahydropyranyloxy or lower alkoxy (C1-C4) with a lithio alanate of the formula:
Li ? III

wherein R2 and R3 are as hereinabove defined; R is alkyl (C1-C7) to give a compound of the formula:

(IV) wherein R5, Z, R6, R2, and R3 are as hereinabove defined, to deblock the ether and ester groups with weak acid to give a compound of the formula:

(V) where R4, Z, R1, R2 and R3 are as hereinabove defined, and where required treating the compound of Formula IV or V with dilute mineral acid to give a compound of the formula:

(VI) wherein R1, R2 and R3 are as hereinabove defined and Z' is selected from the group consisting of (CH2)6, CH2,CH=CH(CH2)3 and-(CH2)4OCH2 and where required treating the compound of Formula V cis with a sterioselective hydride reducing agent to give a compound of the formula:
(VII) wherein R1, R2, R3 and Z are as hereinabove defined and where required treating a compound of Formula V with a hydride reagent to give a compound of the formula:

VIII

wherein R1, R2, R3 and Z are as hereinabove defined, and where required hydrogenating the double bond to give a ccmpound of the formula:

IX

wherein R1, R2, and R3 are as hereinabove defined, Z" is selec-ted from the group consisting of (CH2)6 and (CH2)4-O-CH2 and the moiety ? is selected from the group consisting of:

, and

3. Optically active enantiomers of the Formula I defined in claim 1 and their pharmaceutically acceptable salts, when prepared by the process of claim 1 or or by an obvious chemical equivalent thereof.