CA1095034A

CA1095034A - Process for preparing oxaprostaglandins

Info

Publication number: CA1095034A
Application number: CA173,035A
Authority: CA
Inventors: Michael R. Johnson; Hans-Jurgen E. Hess
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1972-06-02
Filing date: 1973-06-01
Publication date: 1981-02-03
Also published as: IL50311A; CH589074A5; SE7608221L; NO740849L; IE38568L; JPS5231054A; DD124594A5; FI55995B; GB1440603A; JPS5314062B2; IL42373A; SE7608223L; SE415756B; PH11300A; DE2344838B2; CH590224A5; AU5639373A; SE7608222L; ES441002A1; CH586716A5

Abstract

ABSTRACT OF THE DISCLOSURE
.omega.-Trisnorprostaglandins of the formula:

having at the 17-position two hydrogen atoms and one substituent of the formula:
(CH2)n-O-(CH2)mCH3 wherein n is an integer of from 0 to 2, m is an integer of from o to 4; with the proviso that the sum of n and m does not exceed 6; and having at the 15-position one hydrogen substituent or alkyl substituent of from 1 to 3 carbon atoms. The novel prosta-glandins of this invention have been found to have activity pro-files comparable to the parent prostaglandins, but exhibit a greater tissue specificity of action.

Description

1095()3~

This invention relates to certain novel analogs of the naturally occurring prostaglandins and a process for the preparation thereof. In particular, it relates to novel 18-oxa, l9-oxa, 20-oxa, lg-oxa-~--homoprosta-glandins, and various novel intermediates and reagents useful in their preparation.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance, the prostaglandins of the E and A series are potent vaso-10 dilators (Bergstrom, et al., Acta ~ . Scand. 64:332-33, 1965 and Bergstrom, et al., Life Sci. 6:449-455, 1967) and lower systemic arterial blood pressure ~vasodepression) on intravenous administration (Weeks and King, Federation Proc.
23:327, 1964; ~ergstrom, et al ~ 1965, _~. citi Carlson, et 15 al., Acta. Med. Scand. 183:423-430, 1968; and Carlson, et al., Acta Physiol. Scand. 75:161-163, 1969)o Another well known phy~iological action for PGEl and PGE2 i6 as a broncho-dilator (Cuthhert, Brit. Med. J. 4:723-726, 1963).
Still another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE2 is known to possess the ability to induce labor (Karim, et al., J. Obstet G~naec~ Brit. Cwlth. 77:200-210, --1970), to induce therapeutic abortion (~ygdeman, et al., Contraception, 4, 293 (1971~ and to be useful for control of 25 fertility (Karim, Contraception, 3, 173 (1971)~. Patents q~

,.

10~5034 have been obtained for several prostaglandins of the E and F series as inducers of labor in mammals ~elgian Patent 754,158 and West German Patent 2,034,641), and on PGFl, F2, and F3 for control of the reproductive cycle ~South African Patent 69/6089).
Still other known physiological activities for PGEl are in the inhibition of gastric acid secretion ~Shaw and Ramwell, In: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, p. 55-64) and also of platelet aggregation (Emmons, et al., Brit. Med. J. 2:468-472, 1967).
It is now known that such physiological effects will be produced ln vivo for only a short period, following the administration of a prostaglandin. A substanial body of evidence indicates that the reason for this rapid cessation of activi~y is that the natural prostaglandins are quickly and efficiently metabolically deactivated by ~-oxidation of the carboxylic acid side-chain and by oxidation of the 15~-hydroxyl group (Anggard, et al., Acta ~ . Scand., 81, 396 ~1971) and references cited therein).
It was, of course, considered desirable to create analogs of the prostaglandins which would have physiclogical activities equivalent to the natural compoundc, but in which the selectivity of action and the duration of the activity would be increased. Increased selectivity of action would be expected to alleviate the severe side effects, parti-cularly gastrointestinal side effects, frequently observed following systemic administration of the natural prosta-glandins (~ee Lancet, 536, 1971).
In accordance with the present invention thexe is provided a process for preparing a compound of the -.~

~095~34 formula:
M

~ ' \ ~COOH

HO ~/ ( CH 2 ) n~~ (C~2 ) mC~3 OH
H /OH
' wherein M is oxo /" or H

n is 1 or 2 and m is O or 1 when M is oxo 5 and n is 1 or 2 and m is O when H OH
M is / or ~"
'OH H
which comprises hydrolysing a compound of the formula:
1~
f ~ ~ ~ ~COOH I I

THPO~ ~ CH 2 ) n~ ~ ~CH2 ) mCH3 OTHP
where:in M, n and m are as defined above and THP is the tetrahydropyranyl radical by trea~ment with aqueous acetic acid.

1095~)34 Preferred compounds prepared by the process according to this invention are of the formulae:
QH
~ ~` ~ OOH

HO~ ~ ~ ~ (cH2~n~~~cH2)mcH3 OH ... IA
1~
and ~ ~` ~ COOH

HO ~ ~ (CH2)n~~(CH2)mc~3 wherein n and m are as defined above.
Especially preferred novel prostaglandins prepared by the process of this invention are:
9-oxo-lla,15~-dihydroxy-19-oxa-cis-5-trans-13-prostadienoic acid~;
.10.. . 9-oxo-11~,15a-dihydroxy-19-oxa-cis-5-trans-13-~-homoprostadienoic acid;
9-oxo-lla,15a-dihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid, 9cc,lla,150~-trihydroxy-l9-oxa-cls-5-trans-13-prosta-.15 dienoic acid;
9~ ,15a-trihydroxy-lg-oxa-c -5-trans-13-~-homoprostadienoic acid;
9a,11a,15~-trihydroxy-18-oxa-cis-5-trans-13-prosta-dienoic acid.
other novel and useful oxaprostaglandin analogs are the Cg, Cll and C15 esters wherein said esterifying yroup is ~ormyl, ~ alkanoyl having from 2 to 5 carhon . atoms, or benzoyl.

~, lO9S034 The intermediate compound of Formula II above may be prepared by a process which comprises:
a) when M is oxo and n and m, are as defined above, oxidizing a compound of the formula OH

~ ~ ~ ~ OOH II-A

THPO` ~ ~ (CH ) -O-(CH2) CH3 OTHP
wherein n, m and THP are as defined above, with chromic acid, aqueous sulfuric acid and acetone, or b) when M is ~'OH and m, n and THP are as defined above, reacting a compound of the formula _\

THPO~ ~ (cH2)n~~(cH2)mcH3 OTHP
with an ylide of the Formula ( 6 5)3P CH CH2CH2CH2-COOH
The following reaction Scheme illustrates the preparation of the intermediate of Formula II and the conversion of ~he in~erme~iate intQ the prosta-glandin of Formula I..

,~.

lO!~S034 REACTION SCHEME
OH
0~
~ ~ OH

THPO _ (CH2)mCH3 ~ ~ ~ (CH2)n~~
OTHP THP~ _ (CH2)mCH3 III OTHP

Oxaprostaglandin F2~ and E2, of Formula I, "~' ' lO9S034 As shown in the Reaction Scheme III ~ II is brought about by reaction with (4-carbohydroxy-n-butyl)-triphenylphosphonium bromide and methylsulfinylmethide in dimethyl sulfoxide at room tem-perature for at least 2 hours. The mixture is thenacidified with, for example, aqueous hydrochloric acid, and then is extracted with ethyl acetate, evaporated, and concentrated.
II + Oxaprostaglandin F2~ involves hydrolysis with aqueous acetic acid, concentration, and purification by column chromatography.
II ~ Oxaprostaglandin E2 requires treatment with Jones' reagent for about 20 minutes at -10C., to form a second intermediate before ~he acid treatment and purification as above.`

~' lO9S03~

The novel alkanoates, formates, and benzoates of the E and F series of oxaprostaglandins are prepared by reaction of the appropriate prostaglandins with an acid chloride. For example, l9-oxa PGE2 when reacted with benzoyl chloride, in the presence of a tertiary amine in a reaction-inert solvent, will yield 11,15-dibenzoyl-19-oxa PGE2 and, in the same way, 18-oxa PGF2~ when reacted with pivaloyl chloride will yield 9,11,15-tripivaloyl-18-oxa PGF2~.
Analogous reaction sequences can be utilized for the preparation of 20-oxaprostaglandins.
As the literature cited establishes, the natural prostaglandins are known to exhibit a spectrum of phyæiologi-cal activities. In numerous in vivo and ln vitro tests we have demonstrated that the oxaprostaglandin analogs have the same physiological activities as exhibited by the natural prostaglandins. ~hese tests include, among others, a test for effect on isolated smooth muscle from guinea pig ileum _g _ ~Y

and rat uterus, a test for effect on histamine ind~ced broncho-spasm in guinea pig, a test for effects on dog blood pressure, a test for induction of diarrhea in mice, and a test for the induction of abortion in early pregnant rats.
Results on these various physiological tests are shown in Table I below. It will be noted that not only do these oxaprostaglandin analogs possess comparable action quantitatively to the natural prostaglandin, but they also possess the advantage of tissue selectivity, particularly l9-oxaprostaglandin E2. On the basis of the difference seen in the rat uterus and guinea pig ileum tests with l9-oxa-prostaglandin E2, one would expect to have a reduction of the unpleasant gastrointestinal side effects which were en- .
countered when natural PGE2 was employed as an abortion inducer tLancet, 536, 1971). This important advantage has been amply verified by the fact that l9-oxaprostaglandin E2 has now been found to be only 10~ as effective as natural PGE2 in inducing diarrhea in mice in vivo, while it is as effective as natural PGE2 in inducing abortion in the early pregnant rat. Furthermore, as can be seen from Table I, 18-oxa PGE2 is particularly selective with regard to lts blood pressure effect~, while l9-oxa-~-homo PGE2 is a more selec tive bronchodilator than natural PGE2.

,~

,.
0 ~o ~
I ~ ~o ' ' ' ' ~o ~ X X
C~
,, +, ...
I ~ P.
~ ~ 3 P~ o o o o o ,, o ,, ~ o o~ o , , , , , ~q ~ ~ o o o o o o U~ ~
,~ q) O O O O O ,~ 0 ~:
~ ~1 ~1 ~1 ~1 ~I r-l h ~
~ i-l ,~
U
_, q~ ~
cq CU CO
~ O O O O O O æ ~ .
i~ ooooooo ~l O O O O O O ,D ~r~
U~ O O~D O ~1 ~ ~
~1~1 ~ ~~¦

~ ri h >

_ ~ h 0 O ~ O
~O ~ ~ ~ ~
~ o o~ a~ ~ I I I Il~ ~.C ~3 ~1 0 h ~.1 ~,1 O ~P, 6~ 0 ~_~ ~ a~ h ~ '~
~ ~ O O
_~ ~
0 ~ ~ C) CJ ,~
O ~1 ~ h ~ ~ i a~ h O ~ C~J I I I ~1 ~ 0 ~3 c~l o ~
; ~ ~P O ~D ~ O
. ~ ~ O ~0 0~ ~
~ ~ ~ ~ O
~ 8 ,n O S~ h .~1 0 0 c~ a U ~ o o o g ~ O
.~ C~ o o I ~ 3i -I a 0 ~ ~ ~
74 ~ X X ~ E~ H
I O O O OO O N
~0 ~

~, .

10~5034 The physlologlcal responses observed in these tests are useful in determlning the utility of the test substance - for the treatment of varlous natural and pathologlcal condl-tlons. Such determlned utllltles lnclude: antlhypertenslve activity, bronchodilator actlvlty, antlthrombogenic actlvity, antiulcer actlvlty, smooth muscle activity [useful as anti-fertillty agent, for the lnductlon of labor, and as an aborti-faclent], and anti-fertllity activity through a mechanlsm not affecting cmooth muscle, for example, luteolytic mechanlsms.
The novel compounds of thls lnvention posse~s more selective activlty profile~ than the corresponding naturally occurrlng prostaglandins and, ln many cases, exhlbit a longer duration of action. For example, lf an lntravaglnal treat-ment for abortion induction i9 desiredj a suitable vehicle ls a tampon impregnated with l9-oxa-~ -homoprostaglandln F2~ or lactose tablets of the same agent. In such treatments a sult-able dose would be about 100 mg. wlth 1 or 2 doses being em-ployed.
In cases where a mldterm abortlon ls necessary, an effectlve agent would be physlological NaCl solutlon of 19-oxa-PGE2 adminlstered a~ an intravenous infusion. A suitable dosage could be from about 5 to 100 ~g/min admlnistered for a period of from about 2 to 10 hours.
Another use for the oxaprostaglandlns is as an inducer of labor. For this purpose a physlological NaCl solu-tlon of 18-oxa PGF2~ ls employed as an lntravenous infusion in the amount of from about 5 to 100 ~ug/kg/min ~or from about 1 to 10 hours, or 18-oxa PGF2~ ls admlnlstered orally a~ dose~ of 5 to 100 mg. every 2 hours.
Stlll other appllcatlons for the oxapros~aglandins 1~ .
.

are to produce bronchodilation or to increase na~al patency.
An appropriate dosage form for this use is an ethanolic solu-tlon of l9-oxa~L-homo-PGE2 employed as an aerosol using fluorinated hydrocarbons as propellant in the amount of from about 50-500Jug/dos.
Oxaprostaglandins o~ the E series are useful hypotensive agents~ For treatment of hypertension these compounds axe administered as intravenou~
in~ections at doses of about 0.5-10 ~g/kg or preferably orally in the form of capsules or tablets at doses of 0.005 to 0.5 mg/kg/day.

The new compounds of this lnventlon may be u~ed ln a varlety of pharmaceutlcal preparatlons whlch contaln ~' .

the compound or a pharmaceutically acceptable salt thereof, and they may be administered in the same ma~ner as natural prostaglandins by a variety of routes, such as intravenous, oral and topical, including aerosol, intravaginal, and intra-nasal, among others. Pharmaceutically acceptable saltsinclude salts of pharmaceutically acceptable bases such as alkali and alkaline earth metals, ammonia, and amines.
To prepare any of the above dosage forms or any of the numerous other forms possible, various reaction-inert diluents, excipients or carriers may be employed. Such sub-stances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol, and other known carriers for medicament~. If deqired, these pharmaceutical compositions may contain auxiliary substances such as pre~erving agent~, wetting agents, stabilizing agents, or other therapeutic agents, such as antibiotic~.
The following examples are merely illu~trative, and in no way limit the scope of the appended claims.
EXAMPLE I (Starting Material)

2-15a-Hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-~tetrahydro-pyran-2-yloxy]-7-oxa-trans-l-octen-l-yl)cyclopent-l-yl]acet-aldehyde, y-hemiacetal A solution of 310 mg. (0.71 mmole) 2-[5-hydroxy-

3~-ttetrahydropy~an-2-yloxy)-2~-3a-[tetrahydropyran-2-yloxy]
7-oxa-trans-l-octen-l-yl)cyclopent-l~-yl, acetic acid, r-lactone in 5 ml. dry toluene wa~ cooled to -78 in a dry nitrogen atmosphere. To this cooled solution was added l.5 ml. of 20~ diisobutylaluminum hydride in n-hexane dropwise at .T~

such a rate so that the internal temperature never rose about -65 (15 minutes). After an additional 45 minutes of stir-ring at -7%, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml.
ether, washed with 50% sodium potassium tartrate solution (4 x 20 ml.), dried ~MgSO4) and concentrated to yield 290 mg.
(93%) 2-[5a-hydroxy-3~-(tetrahydropyran-2-yloxy)-2~-(3~-[tetrahydropyran-2-yloxy]-7-oxa-trans-1-octen-1-yl)cyclopent-l-yl]acetaldehyde, y-hemiacetal.
EXAMPLE II
9a-Hydroxy-11,15~-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadienoic acid _ To a solution of 810 mg. (2.0 mmole) (4-carbo-hydroxy-n-butyl)triphenylphosphonium bromide in a dry nitro-gen atmosphere in 5.0 ml. dry dimethyl sulfoxide was added 2.0 ml. (4.4 mmole) of a 2.2M solution of sodium methyl-sulfinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 290 mg. (0.66 mmole~
2-~5a-hydroxy-3~-(tetrahydropyran-2-yloxy)-2~-(3a-[tetrahydro-pyran-2-yloxy~-7-oxa-trans-1-octen-1-yl)cyclopent-la-yl]-acetaldehyde, y-hemiacetal as prepared in Example I in 3.0 ml. dry dimethyl sulfoxide over a period of 20 minutes.
After an additional 2 hours stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (20 ml.) and acidified to pH - 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml.) and the combined organic extr~cts washed once with water (10 ml.), dried (MaSO4) and evaporated to a solid ., ~,~
.,~.

residue weighing 784 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed"
Reagent 60-200 mesh) using ethyl acetate as eluent. After removal of high Rf impurities, 225 mg. (66~) of 90~-hydroxy-llc~,15a-bis- (tetrahydropyran-2-yloxy)-l9-oxa-ci9-5-trans-13-prostadienoic acid was collected.
The nmr spectrum (CDC13) exhibited a multiplet (variable) at 5.84-6.38 ~ (2H) for the -OH protons, a multi-plet at 5.27-5.68 s ~4H) for the olefinic protons, a multi-plet at 4.52-4.84 s (2H) for the acetal protons, a singlet at 3.34 s (3H) for the methyl ether protons and nmltiplets at 3.25-4.35 s (9H) and 1.20-2~72 s (28H) for the remaining pr~tons.
EXAMPLE III
9-Oxo-lla,15a-bis- (tetrahydropyran-2-yloxy)-19-oxa-cls-5-trans-13-prostadienoic acid ., .
To a solution cooled to -10, under nitrogen of 190 mg. (0.356 mmole) 9~-hydroxy-lla,15a-bis- (tetrahydro-pyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadienoic acid as prepared in Example II, in 5 ml. reagent grade acetone was added dropwise 0.143 ml. (0.356 mmole) of Jones' reagent.
After 20 minutes at -10, 0.140 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minuteQ at which time it was combined with 40 ml. ethyl acetate, washed with water (3 x 5 ml.), dried (MgSO4) and concentrated to give 174 mg. of 9-oxo-lld~,15d~-bis- (tetra-hydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadienoic acid.

109503q~
EXAMæLE IV
9-Oxo-lla,15~-dihydroxy-19-oxa-cls-5-trans-13-prostadienoic a_ A solution of 174 mg. (0.334 mmole) 9-oxo-1~X,15~-bis-tetrahydropyran-2-yloxy)-19-oxa-cls-5-trans-13-prosta-dienoic acid as prepared in Example III in 3.0 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitro-gen at 40 for 5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate as eluent. ~fter elution of less polar impurities the semisolid 9-oxo-lld,15~-dihydroxy-19-oxa-cls-5-t~E~a_-13-prostadienoic acid weighing 33 mg. was collected. This product is l9-oxaprostaglandin E2, m.p.
lS 58-9 (ethyl acetate, cyclohexane~.
Analysis: Calc'd for C - 64.39; H - 8.53 Found: C - 64.30; H - 8.28 [a] = -71.2 (C = 1.0, methanol) The ir spectrum (CHC13) of the product exhibited a strony adsorption at 1715 cm 1 for the carbonyls and a medium band at 965 cm~l for ~he trans double bond. The uv spectrum in methanol with added potassium hydroxide solution exhibited a ~max 278 m~ and an Emax 28,000.

EXAMPLE V
9,11a,15a-Trihydroxy-cis-5-trans-13-prostadienoic acid A solution of 52 mg. (0.10 mmole) 9a-hydroxy-,~..

lla,15-bis-(tetrahydropyran-2-yloxy)-19-oxa-cl~-5-trans-13-prostadienoic acid as prepared in Example II, in 3.0 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 40 for 5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl then methanol as eluents. After elution of less polar impurities the oily 9a,11~,15~-trihydroxy-cis-5-trans-13-prostadienoic acid weighing 15 mg. was collected. Thi~ product i8 l9-oxo-prostaglandin F~a.
EXAMPLE VI (Starting Material) 2-~5a-Hydroxy-3a-(tetr_h~ro~ran-2-ylox~)~2~-(3a-[tetrahydro-pyran-2-yloxy~-7-oxa-trans-1-nonen-1-yl)cyclopent-1-yl]acet-aldehyde, y-hemiacetal A solution of 575 mg. (1.28 mmole) crude 2-~5~-hydroxy- 3a- te~rahydropyran- 2- yloxy) - 2~- (3~- [tetra-hydropyran~2- yloxy]- 7- oxa trans~ 1 nonen- 1- yl) cyclopent~ la--yl, acetic acid, yo lactone in 5.75 ml. dry toluene was cooled to -78 in a dry nitrogen atmosphere. To this cooled solution was added 1.8 ml. of 20~ diisobutyl-aluminum hydride in n-hexane dropwise at ~uch a rate so that the internal temperature never rose above -65 (15 minutes~.
After an additional 1 hour of ~tirring at -78, anhydrous methanol was added until gas evolution ceased and the reac-tion mixture was allowed to warm to room temperature. Thereaction mixture was combined with ;0 ml. ether, washed with 50% sodium pota~sium tartrate solution (4 x 10 ml.), dried (MgSO4) and concentrated to yield 458 mg. (80%) 2-[5a-hydroxy-3a-(tetrahydroxypyran-2-yloxy)-2~-(3~-~tetrahydropyran-2-yloxy]-7-oxa-trans-1-nonen-1-yl)cyclopent-1-yl]acetaldehyde, .'''~ .

:1095~34 y-hemiacetal.
EXAMPhE VII
9a-Hydroxy-ll~,15~-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-~-homo-prostadienoic acid.
To a solution of 1,330 mg. (3.0 mmole) (4-carbo-hydroxy-n-butyl)triphenylphosphonium bromide in a dry nitro-gen atmosphere in 6 ml. dry dimethyl Qulfoxide was added 3.4 ml. (6.8 mmole) of a 2.OM solution of sodium methylsulfinyl-methide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 454 mg. (1.0 mmole) crude 2-~5a-hydroxy-3-(tetrahydropyran-2-yloxy)-2~-(3a-[tetra-hydropyran-2-yloxy]-7-oxa-trans-1-nonen-1-yl)cyclopent-la-yl~acetaldehyde, y-hemiacetal as prepared in Example VI in 3.0 ml. dry dimethyl sulfoxide over a period of 20 minutes.
After 2 hours stirring at room temperature, the reaction mixture was poured onto ice water. The basic a~ueous solu-tion was washed twice with ethyl acetate (30 ml.) and acidi-fied to pH - 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (4 x 25 ml.) and the combined organic extracts washed once with water (25 ml.), dried ~MgS04) and evaporated to a solid residue weighing 900 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate wa~ purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) u~ing ethyl acetate as eluent. After removal of high Rf impurities, 290 mg. (54%) of 9~-hydroxy~ ,15~-bi~-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-~-homo-prostadienoic acid was collected.
The nmr ~pectrum ~CDC13) exhibited a multiplet (variable) at 6.2-6.6 ~ (2H) for the -OH protons, a multiplet at 5.3-5.7 ~ (4H) for the olefinic protons, a multiplet at

4.6-4.9 ~ (2H) for the acetal protons, a quartet at 3.5 (2H) for the ethyl ether protons and multiplets at 3.3-4.4 (9H) and 1.0-2.6 ~ (31H) for the remaining protons.
EXAMPLE VIII
9-Oxo-11~,15a-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-~-homoprostadienoic acid _. _ _ _ To a solution cooled to -10, under nitrogen of 290 mg. (0.540 mmole) 9~-hydroxy~ ,15~-bis-(tetrahydropyran-2-yloxy)-19-oxa-cls-5-trans-13-~-homoprostadienoic acid, as prepared in Example VII in 5.4 ml. reagent grade acetone was added dropwise 0.226 ml. (0.600 mmole) of 2.67M Jones' reagent. After 5 minutes at -10, 0.230 ml. 2-propanol was added and the reaction mlxture was allowed to stir an addi-tional 5 minutes at which time it was combined with 30 ml.
ethyl acetate, washed with water ~3 x 5 ml.), dried ~MgSO4i, concentrated, and chromatographed (~aker 60-200 mesh silica gel, CH2C12 eluent) to give 180 mg. of 9-oxo-11~,15~-bis-~tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-~-homo-prostadienoic acid.
EXAMPLE IX
9-Oxo~ ,15a-dihydroxy-19-oxa-cic-5-trans-13-~-homo-prosta-dienoic acid A solution of 129 mg. (0.240 mmol~) 9-oxo-11,15a-b~s-tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-~-homo-pro~tadienoic acid, as prepared in Example VIII, in 3.0 ml.
of a 65:35 mixture of glacial ~cetic acid:water was stirred under nitrogen at 4Q for 2.5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4 100-109503~

200 mesh) using ethyl acetate as eluent. After elution of less polar impurities 9-oxo-11~,15~-dihydroxy-19-oxa-cls-5-trans-13-~-homoprostadienoic acid weighing 40 mg. was collected (m.p. 56-7). This product is l9-oxa-~-homo-prostaglandin E2.
The uv spectrum in methanol with added potassiumhydroxide solution exhibited a ~ max 278 m~ and an ~ max 25,700.

If l9-oxa-~-homoprostaglandin F2a is desired, the procedure outlined in Example V may be followed, using the product of Example VIII as a starting material.
EXAMPLE X (Starting Material) 2-~5~-Hydroxy-3~-(tetrahydropyran-2-yloxy)-2~-(3-[tetra-hydropyran-2-yloxy]-6-oxa-trans-1-octen-1-yl)cyclopent-1-- 15 yl]acetaldehyde, ~-hemiacetal A solution of 880 mg. ~2.01 mmole) crude 2-[5a-hydroxy-3a-tetrahydropyran-2-yloxy)-2~-~3a-[tetrahydro-pyran-2-yloxy]-6-oxa-trans-1-octen-1-yl)cyclopent-1~-yl, acetic acid, y-lactone in 8.8 ml. dry toluene was cooled to 2a -78 in a dry nitrogen atmosphere. To this cooled solution was added 3 ml. of 20% diisobutylaluminum hydride in n-hexane dropwise at such a rate so that the internal tempera-ture never rose about -65 (15 minutes). After an additional 30 minutes of stirring at -78, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml. ether, washed with 50% sodium potassium tartrate solution (~ x 10 ml.), dried (MgS04) and concentrated to yield 654 mg. 2-[5a-hydroxy-3-(tetrahydro-pyran-2-yloxy)-2~-(3~-[tetrahydropyran-2-yloxy]-6-oxa-trans-l-octen-l-yl)cyclopent-l-yljacetaldehyde, y-hemiacetal.
EXAMPLE XI
9a-Hydroxy-lla,l5~_bis_(tetrahydropyran-2-yloxy)-18-oxa-cis-

5-trans~13-prostadienoic acid To a solution of 2,600 mg. (6.0 mmole) (4-carbo-hydroxy-n-butyl)triphenylphosphonium bromide in a dry nitro-gen atmosphere in 6 ml. dry dimethyl sulfoxide was added

6.0 ml. (12.0 mmole) of a 2.OM solution of sodium methyl-sulfinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 660 mg. (1.5 mmole) crude 2-[5-hydroxy-3~-~tetrahydropyran-2-yloxy)-2~- -(3~-[tetrahydropyran-~-yloxy]-6-oxa-trans-1-octen-1-yl)cyclo-~ent-la-yl]acetaldehyde, r-hemiacetal, prepared as in Example X in 5.0 ml. d~y dimethyl sulfoxide over a period of 20 minutes. After an additional 2 hours stirring at room tem-perature, the reaction mixture was poured onto ice water.
The basic a~ueous solution was washed twice with ethyl acetate (100 ml.) and acidified to p~ ~ 3 with 10~ aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 100 ml.) and the combined organic extracts washed once with water t25 ml.), dried (MgS04) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using ethyl acetate as eluent. After removal of bigh Rf impurities, 550 mg. (70%) of 9~-hydroxy~
bis-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prosta-dienoic acid was collected.

~0~5034 The nmr spectrum (CDC13) exhibited a multiplet (variable) at 6.2-6.6 ~ (2H) for the -OH protons, a multiplet at 5.3-5.7 ~ (4H) for the olefinic protons, a multiplet at 4.6-4.9 ~ (2H) for the acetal protons, a quartet at 3.5 (2H) for the ethyl protons and multiplets at 3.3-4.4 ~ (9H) and 1.0-2.6 ~ (31H) for the remaining protons.
EXAMPLE XII
9-Oxo~ ,15a-bis-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadienoic acid To a solution cooled to -10 under nitrogen of 400 mg. (0.765 mmole) 9a-hydroxy-11~,15~-bis-(tetrahydro-pyran-2-yloxy)-18-oxa- Q -5-trans-13-prostadienoic acid, prepared as in Example XI in 8 ml. reagent grade acetone was added dropwise 0.338 ml~ (0.900 mmole) of 2.67M Jones' reagent. After 5 minutes at -10, 0.350 ml. 2-propanol was added and the reaction mixture was allowed to stir an addi-tional 5 minutes at which time it was combined with 60 ml.
ethyl acetate, washed with water (3 x 5 ml.), dried (MgSO4), and concentrated to give 280 ms. of 9-oxo-11~,15~-bls-(tetra-hydropyran-2-yloxy)-18-oxa-cls-5-trans-13-prostadienoic acid.
E~AMPLE XIII
9-Oxo-11~,15~-dihydroxy-18-oxa-cls-5-trans-13-prostadienoic acid A solution of 280 mg. (0.240 mmole) 9-oxo-llo~l~X-bis-~etrahydropyran-2-yloxy) 18-oxa-cis-5-trans-13-prosta-dienoic acid, prepared as in Example XII in 4.0 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 40 for -2.5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel ~Mallinckrodt CC-4 100-200 mesh) 1095t)34 using ethyl acetate as eluent. After elution of less polar impuritie~ the oily 9-oxo~ ,15~-dihydroxy-18-oxa-cls-5-tra_ -13-prostadienoic acid weighing 66 mg. wa~ collected.
This product is 18-oxaprostaglandin E2.
The uv spectrum in methanol with added potassium hydroxide solution exhibited a ~max 278 m~ and an ~max 23,800 to 25,600.
EXAMPLE XIV
9~,11~15~-Trihydroxy-18-oxa-cis-5 trans-13-prostadienoic acid A solution of 75 mg. (0.10 mmole) 9~-hydroxy-llot,15~-bls-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-pro~tadienoic acid, prepared as in Example XII, in 3.0 ml.
of a 65:35 mixture of glacial acetic acid:water was ~tirred under nitrogen at 40 for 5 hour~ then wa3 concentrated by rotary evaporation. The resultant crude oil was purified on silica g~l (Mallinckrodt CC-4 100-200 mesh) using ethyl then methanol as eluents. After elution of less polar impuri~ies the oily 9~ ,15~-trihydroxy-18-oxa-cis-5-tran~-13-prostadienoic acid weighing 20 mg. was collected. This product i~ 18 oxaproYtaglandin F2~.
EXAMPLE XV (Starting Material) 2-[5~-Hydroxy-3~-(tetrahydropyran-2-yloxy)-2~ -[tetra-hydropyran-2-yloxy]-8-oxa trans- -nonen-l-yl)cyclopent-l~ryl]-acetaldehyde, y-hemiacetal A ~olution o~ 900 mg. (2.G mmole) 2~ hydroxy-3~-(tetrahydropyran-2-yloxy)-2~ (3~[tetrahydropyran-2-yloxy~-8-oxa-tran~-1-nonen-1-yl)cyclopent-~-yl3acetic acid, Y-lactone in 15 ml. dry toluene was cooled to -78 in a dry nitrogen atmosphere. To this cooled solution was added 2.7 ml. of 20% diisobutylaluminum hydride in n-hexane ~Aifa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65 (15 minutes~. After an additional 45 minutes of stirring at -78, anhydrous acetic acid was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reac-tion mixture was combined with 60 ml. toluene, washed with 50% sodium potassium tartrate solution (1 x 25 ml.), dried (Na2SO4) and concentrated to yield 564 mg. 2-~5~-hydroxy-3~-(tetrahydropyran-2-yloxy)2~ (3~tetrahydropyran-2-yloxy]-8-oxa-trans-l-nonen-l-yl)cyclopent-l-yl3acetaldehyde, y-hemi-acetal, after chromatography.

ExAMæLE XVI (S~arting Material) 2-[5~-Hydroxy-3~-(te~rahydropyran-2 yloxy)-2 ~ t3~-[tetra-hydropyran-2-yloxyj-8-oxa-trans-1-nonen-1-yl)cyclopent-1~-yl~acetaldehyde, ~-hemiacetal.
. - ~
A solution of 3.5 g. (7.75 mmole) 2-~5~-hydroxy-3~-ttetrahydropyran-2-yloxy)-2~ [tetrahydropyran-2-yloxy]-8-oxa~trans-1-nonen-1-yl~cyclopent-1~-yl]acetic acid, Y-lactone in 25 ml. dry toluene was cooled to -78 in a dry nitrogen atmosphere. To this cooled ~olution was added 10.5 ml. of 20~ diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal t~m-perature never rose above -65 tl5 minutes). After an addi-tional 45 minute~ of stirring at -78, acetic acid in toluene was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mix-ture was combined wit`n 100 ml. ether, washed with 50% sodium ~' .
.

potassium tartrate solution (1 x 50 ml.), dried (Na2SO4) and concentrated to yield 2.6 g. 2-[5~-hydroxy-3~-(tetrahydro-pyran-2-yloxy)-2~ (tetrahydropyran-2-yloxy]-8-oxa-trans-l-nonen-l-yl)cyclopent-l-yl]acetaldehyde, y-hemiacetal after chromatography.
EXAMPLE XVII

5-trans-13-~-homoprostadienoic acid To a solution of 7.65 g. (17.25 mmole) (4-carbo-hydroxy-n-butyl)triphenylphosphonium bromide in a dry nitro-gen atmosphere in 20 ml. dry dimethyl sulfoxide was added 15.3 ml. (32.2 mmole) of a 2.lM solution of sodium methyl-sulfinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 2.6 g. (5.76 mmole) 2-~5~-hydroxy-3~-(tetrahydropyran-2-yloxy)-2~-(3~-[tetra-hydropyran-2-yloxy]-8-oxa-trans-1-nonen-1-yl)cyclopent-1~-yl]acetaldehyde, ~-hemiacetal in 15.0 ml. dry dimethyl sulfoxide over a period of 20 minutes. After an additional 2 hours stirring at room temperature, the reaction mixture was poured onto ice water (60 mls.), 250 ml. ethyl acetate and 35 ml. lN HCl. The acidic solution wa~ further extracted with ethyl acetate (2 x 120 ml.) and the combined organic extracts washed once with water (60 ml.), dried (MgSO4) and evaporated to a residue. The residue was purified by column chromatography on silica gel (Baker "Analyzed" RPagent 60-200 mesh) using ethyl acetate as eluent. After removal of high Rf impurities, 3.1 g. of 9~-hydroxy-1~,15~-bls-(tetrahydro-pyran-2-yloxy)-20-oxa-cls-5-trans-13-~-homoprostadienoic acid was collected.

jf ;~, .
' ~.
~ s 10~5034 9~-Hydroxy~ ,15~-bls-(tetrahydropyran-2-yloxy)-20-oxa-cis-5-trans-13-~-homoprostadienoic acid To a solution of 2120 mg. (5.0 mmole) (4-carbo-hydroxy-n-butyl)triphenylphosphonium bromide in a dry nitro-gen atmosphere in 8.0 ml. dry dimethyl sulfoxide was added 5.02 ml. (9.3 mmole) of a 1.85M ~olution of sodium methyl-sulfinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 564 mg. (1.22 mmole) 2-(S~-hydroxy-3~-(tetrahydropyran-2-yloxy)- ~-( ~
~tetrahydropyran-2-yloxy]-8-oxa-trans-1-nonen-1-yl)cyclopent-l~-yl]acetaldehyde, ~-hemiacetal in 5.0 ml. dry dimethyl sulfoxide over a period of 20 m~nutes. After an additional 2 hour~ stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueouq solution was extracted with ethyl acetate (2 x 100 ml.) and the combined organic extracts washed once with water (40 ml.), dried (MgSO4) and evaporated to a residue. This residue was puri-fied by column chromatography on silica gel (Baker "Analyzed"
Reagent 60-200 mesh) using chloroform ethyl acetate as eluents. A~ter removal of high Rf impurities, 642 mg. of 9~-hydroxy-11x,15~-bls-(tetrahydropyran-2-yloxy)-20-oxa-cls-5-trans-13-~-homopro3tadienoic acid was collected.
EXAMPLE XIX
9-Oxo-lL~,15~-bis-(tetrahydropyran-2-yloxy)-20-oxa-cis-5-trans 13-~-homoprostadienoic acid To a solution cooled to -10~ under nitrogen of 642 mg. ~1.19 mmole~ 9~-hydroxy~ ,15~ bis-(tetrahydropyran-2-yloxy)-20-oxa-cis-5-tran_-13-~thomoprostadienoic acid in 20 ml. reagent grade acetone was added dropwise to 0.59 ml.

1095(~34 (1.58 mmole) of Jones' reagent. After 20 minutes at -10~, 0.6 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 80 ml. ethyl acetate, washed with water (3 x 15 ml.), dried (MgSO4) and concentrated to give 578 mg. of 9-oxo-110~,15,~bis (tetrahydropyran-2-yloxy)-2û-oxa-cls-5-trans-13-~-homoprostadienoic acid.
EXAMPLE XX
9-Oxo-11~,15 -bis-(tetrahydropyran-2-yloxy)-20-oxa-cls-5-trans-13-y~homoprostadienoic acid -To a solution cooled to 15 under nitrogen of 2,000 mg. (3.72 mmole) 9~-hydroxy-11~,15~-bis-(tetrahydro-pyran-2-yloxy)-20-oxa- Q -5-trans-13-~homoprostadienoic acid in 50 ml. reagent grade acetone was added dropwise to 1.85 ml. (0.655 mmole) of 3OneS' reagent. After 20 minutes a -10, 1.~5 ml. 2-propanol wa~ added and the reaction mix-ture was allowed to stir an additional 5 minutes at which time it was combined with 125 ml. ethyl acetate, washed with water (3 x 25 ml.), dried (MgSO4~ and concentrated to give 2.1 g. of 9-oxo~ ,15~-bls-(tetrahydropyran-2-yloxy)-20-oxa-cis-5-tran~-13 ~-tetranorprostadienoic acid.
EXAMPLE XXI
.
9-Oxo~ ,15~-dihydroxy-20-oxa-cis-5-trans-13-~-homopro~ta_ diensic acid A solution of 2,100 mg. (3.29 mmole) 9-oxo-11~,15~-bis-tetrahydropyran-2-yloxy)-20-oxa-cls-5-trans-13-~ omo-prostadienoic acid in 21 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at room tempera-ture for 16.5 hours then was concentrated by rotary evapora-tion. The resultant crude oil was purified by column chroma-~0!95034 tography on silica gel tMallinckrodt CC-7) using chloroform and ethyl acetate as eluents. After elution of less polar impuri~ies the oily 9-oxo-11~,15~-dihydroxy-20-oxa-c1s-S-trans-13-~-homoprostadienoic acid weighing 369 mg. was collected.
EXAMPLE XXII
9-Oxo-11~,15~-dihydroxy-20-oxa-cis-5-trans-13-~-homoprosta--dienoic aci~
A solution of 578 mg. (1.08 ~ole) 9-oxo-11~,15~-bis-tetrahydropyran-2-yloxy)-2o-oxa-cis-5-trans-l3-u/-homo-prostadienoic acid in 3.0 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nit~ogen at 25 for 24 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by col~mn chromatography on silica gel (Mallinckrodt CC-7) using chloroform and ethyl acetate as eluents. After elution of less polar impurities the semisolid 9-oxo-11~,15~-dihydroxy-20-oxa-cis-5-trans-13-~homoprostadienoic acid weighing 131 mgO was collected.
ExAMæLE XXIII

dienoic acid A solution of 800 mg. (1.49 mmole) 9~-hydroxy-llq~, 15q-bls-tetrahydxopyran-2-yloxy)-20-oxa-cis-5-tran~-13-~ homoprostadienoic acid in 3.0 ml. of a 6S:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25 for 16 hours then was concentrated by rotary evaporation.
The resultant crude oil was purified by column chroma-tography on silica gel ~Mallinckrodt CC-7) using ethyl acetate and ethyl acetate/methanol as eluents. After elu-.Y

tion of less polar impurities the oil 9~ ,15~-trihydroxy-20-oxa-cls-5-trans-13-~-homoprostadienoic acid weighing 335 mg. was collected.
EXAMPLE XXIV
9~,11~,1~-Tris-pivaloyloxy l9-oxa PGF2~
To a solution of 76 mg. of l9-oxa-PGF~ in 1.0 ml.
of pyridine is added 120 mg. (1.0 mmole) of pivaloyl chloride.
The solution is stirred for 5 hours at 45 under nitrogen then is cooled to room temperature. To the solution is then added 36 mg. (2.0 ~moles) of water. The solution is then stirred at room temperature for 2.0 hours, then is diluted with ethyl acetate. The diluted solution is washed with O.lN hydrochloric acid (3x), with water (lx), and with saturated ~rine (lx), is dried (anhydrous magnesium sulfate), and is concentrated. Purification of the crude residue by silica gel chromatography provides the desired 9~,11~,1~-tris-pivaloyloxy l9-oxa PGF2~.

EXAMPLE XXV
ll~x,l5~-bis-pivaloyloxy 19-oxat~-homo-PGE2 -To a solution, cooled in ice under nitrogen, of 75 mg. of 19-oxa-~-homo-PGE2 in 1.5 ml. of methylene chlor-ide is added 350 ,ul of pivaloyl chloride followed by 450 ,ul.
of triethylamine. After being stirred at room temperature for 5 hours the mixture is poured onto a mixture of ethyl acetate/ice. The aqueous layer is extracted with ethyl acetate; the combined organic extracts are washed with 10%
hydrochloric acid, with saturated bicarbonate, with water, is dried ~anhydrous magnesium sulfate3, and is concentrated.
Purification of thP crude product by chromatography provides the desired 11~,15~-bis-pivaloyloxy 19-oxa-~Lhomo-PGE2.
.

1~ , 10~5034 EXAMPLE XXVI
l9-Oxa-PGF2~ and l9-oxa-PGF ~
To a solution, cooled in ice, of 35 mg. of l9-oxa-PGE2 prepared in Example IV in 7 ml. of absolute methanol is added an ice-chilled solution of 105 mg. of sodium borohydride in 12 ml. of absolute methanol. The solution is stirred under nitrogen for 20 minutes at 0-5 then for 1.0 hour at room temperature. The reaction mixture is then cooled in ice, 2 ml. of water is added, and the resultant solution is concentrated. The concentrated mixture is overlaid with ethyl acetate, acidified with 10% hydrochloric acid, and the acidified aqueous layer is extracted with ethyl acetate (4 x 5 ml.). The combined extracts are washed with water and saturated brine, dried (anhydrous magnesium sulfate), and concentra~ed. The crude residue is purified by column chroma-tography (Mallinckrodt CC-7) using mixtures of methanol in methylene ch:Loride as eluents to afford l9-oxa-PGF2d~and 19-oxa PGF2~-E~AE~LE XXyII

9 ~-~ydxoxy-11~,15~-bls-(Tetrahydropyran-2-yloxy)-19-oxa-prostanoic acid A heterogenous solution of ~ hydroxy-11~15~-bis-(tetrahydropyran-2-yloxy)-cis-5-trans-13-19-oxaprosta-dienoic acid and 5~ palladium on carbon in methanol is hydrogenated at 0 for ~ hours (1 atm.). The reaction mix-ture is filtered and evaporated to yield the desired product.--3~-- .., ~ ..
~, EXAMPLE XXVIII
9~-Hydroxy-11~,15~-bis-(tetrahydropyran-~-yloxy)-13-trans-19-.
oxaprostenoic acid A heterogeneous solution of 9~-hydroxy-11~,15~-bis-(tetrahydropyran-2-yloxy)-cis-5-trans-13-19-oxaprostadienoic acid and 5% palladium on carbon in methanol is hydrogenated at -22 for 4 hours (1 atm.). The reaction mixture is filtered and chromatographed to yield the desired product.

~ .

Claims

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

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

wherein M is oxo or n is 1 or 2 and m is 0 or 1 when M is oxo and n is 1 or 2 and m is 0 when M is or which comprises hydrolysing a compound of the formula:- II

wherein M, n and m are as defined above and THP is the tetrahydropyranyl radical by treatment with aqueous acetic acid.

2. A process according to claim 1 for preparing 9-oxo-11.alpha.,15.alpha.-dihydroxy-19-oxa-cis-5-trans-13-prostadienoic acid, which comprises treating 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadienoic acid with aqueous acetic acid.

3. A process according to claim 1, wherein the compound prepared is 9-oxo-11.alpha.,15.alpha.-dihydroxy-19-oxa-cis-5-trans-13-.omega.-homoprostadienoic acid, which comprises treating 9.alpha.-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-.omega.-homoprostadienoic acid with aqueous acetic acid.

4. A process according to claim 1, wherein the compound prepared is 9-oxo-11.alpha.,15.alpha.-dihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid, which comprises treating 9-oxo-11.alpha.,15a-bis-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadienoic acid with aqueous acetic acid.

5. A process according to claim 1, wherein the compound prepared is 9.alpha.,11.alpha.,15.alpha.-trihydroxy-19-oxa-cis-5-trans-13-prostadienoic acid, which comprises treating 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadienoic acid with agueous acetic acid.

6. A process according to claim 1, wherein the compound prepared is 9.alpha.,11.alpha.,15.alpha.-trihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid, which comprises treating 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadienoic acid, with agueous acetic acid.

7. The products named in claims 2, 3 or 4 as the compound prepared when prepared by the process of claims 2, 3 or 4 respectively.

8. The products named in claims 5 or 6 as the compound prepared when prepared by the process of claims 5 or 6 respectively.