DK143498B - OXAPROSTAGLANDIN COMPOUNDS OF E2 OR F2AL FARACET FOR USE AS FERTILITY CONTROLS - Google Patents

Description

(19) DENMARK

(12) PRESENTATION Dij (1431) -98 B

DIRECTORATE OF THE PATENT-OO TRADE MARKET

(21) Application no. 5059/75 (51) lnt.CI.3 C 07 C 177/00 (22) Filing day 1 · jun. 1975 A 61 | (31/557 (24) Running Day 1 · Jun 1975 (41) Aim Available 5 · Dec 1975 (44) Submitted 51 · Aug 1981 (86) International Application No - (86) International Filing Day - (85) Continuation Day - (62) Stock Application No. -

(30) Priority Jun 2 1972, 259215 * US 50 Apr 1975, 555644, US

(71) Applicant PFIZER INC., New York, US.

(72) Inventor Michael Rose Johnson, US: Hans-Jurgen Ernst Hess, US.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Oxaprostaglandin inhibitions of the E2 or F2alfa series for use as fertility control agents.

This invention relates to novel oxaprostaglandin compounds of the E2 or F2a series for use as fertility control agents. These compounds are analogous to the naturally occurring process taglandins and are peculiar in that they have the formula I specified in the characterizing part of the claim.

D

The prostaglandins are unsaturated C₂Q fatty acids which exhibit different physiological effects. For example, the prostaglandins of β of the E and A series are potent vasodilators (Bergstrom, et al.,

Acta Physiol. Scan. 64: 552-55, 1965 and Bergstrom, et al., T 3 2 143498

Life Sci. 6: 449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration (Weeks and King, Federation Froc. 23: 327, 1964; Bergstrom, et al., 1965, op. Cit; Carlson, et al. , Acta. Med. Scand. 183: 423-430, 1968; and Carlson, et al., Acta Physiol. Scand. 75: 161-169, 1969).

Another well-known physiological effect of PGE- and PGE2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4: 723-726, 1969).

Another important physiological role of the natural prostaglandins plays in the reproductive cycle. PGEg is known to have the ability to induce labor (Karim, et al., J. Obstet Gynaec. Brit. Cwlth. 77: 200-210, 1970), to induce therapeutic abortion (Bygdeman, et al., Contraception, 4, 293 (1971)) and to be useful for controlling fertility (Karim, Contraception, 3, 173 (1971)). Patents have been obtained on several prostaglandins of the E and F series as mammalian web developers (Belgian patent no.

754 158 and West German Patent No. 2 034 641) and on FGF ^, F £ and F ^ for control of the reproductive cycle (South African Patent No. 69/6089).

Other known physiological activities for PGE1 are through the inhibition of gastric acid secretion (Shaw and Ramwell, in Worcester Symp. On Prostaglandins, New York, Wiley, 1968, pp. 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 in vivo will only be induced for a short time after the administration of a prostaglandin. A substantial amount of testimony indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are rapidly and efficiently metabolically deactivated by β-oxidation of the carboxylic acid side chain and by oxidation of the 15α-hydroxy group (Anggard, et al., Acta. Physiol. Scand , 81, 396 (1971) and references cited therein).

Of course, it was considered desirable to provide analogs to the prostaglandins, which would have equivalent physiological activities with the natural compounds, but at which the selectivity and duration of activity would be increased. Increased efficacy selectivity could be expected to alleviate the serious side effects, especially gastrointestinal side effects, which are frequently observed after systemic administration of the natural prostaglandins (see Lancet, 536, 1971).

The novel compounds of the invention are u-trisnor-prostaglandins, which at the 17-position have two hydrogen atoms and one substituent of formula (CH 2) n ~ 0 '' where n is 0 or 1 and m is 0, 1 or 2. These compounds uniquely satisfy the above requirements, viz. they have activity profiles comparable to those of natural prostaglandins, although they are more tissue selective in their action and exhibit longer duration of activity than natural prostaglandins.

Particularly preferred, novel prostaglandins of the invention are: 9-oxo-11α, 15α-dihydroxy-19-oxa-cis-5-trans-13-prostadioic acid; 9-oxo-11a, 15a-dihydroxy-19-oxa-cis-5-trans-13-uu-homoprostatic acid; 9-oxo-lla, 15a-dihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid; 9a, 11a, 15a-trihydroxy-19-oxa-cis-5-trans-13-prostadienoic acid; 9a, 11a, 15a-trihydroxy-19-oxa-cis-5-trans-13 -> - homoprostadienic acid; 9a, lla, 15a-trihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid.

The preparation of the novel oxaprostaglandin compounds of the invention can be elucidated by the following reaction scheme, wherein R is hydrogen, 2-tetrahydropyranyl or -CO-R, where R is alkyl of 1-5 carbon atoms, phenyl or p-biphenyl , THP means 2-tetrahydropyranyl, and n and m have the meaning set forth in the claim.

4 143498

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As shown in the reaction scheme, the aldehyde I is reacted with the novel reagent II to form the ketone III. The reactants are used in substantially equimolar ratios, and the reaction is preferably carried out for approx. 30 minutes.

The ketone III is treated with 1,2-dimethoxyethane and zinc borohydride for approx. 1 hour to form the alcohols IV and V which are then separated, e.g. using column chromatography with ether as the eluent.

V - * VI involves treatment with anhydrous potassium carbonate for approx.

1 hour followed by hydrochloric acid and extraction, e.g. with ethyl acetate, and finally concentration, VI - * VII requires treatment with 2,3-dihydropyran and p-toluene sulfonic acid for approx. 15 minutes in a nitrogen atmosphere and subsequent combination with ether, washing with e.g. sodium bicarbonate solution and then with brine and final concentration.

VII -> VIII is carried out by reaction for approx. 1 hour with diisobutyl aluminum hydride in n-hexane cooled to -78 ° C in a nitrogen atmosphere. The mixture is then mixed with ether, washed, dried and concentrated.

VIII - IX is reacted with (4-carboxy-b-butyl) -triphenylphosphonium bromide and methylsulfinylmethide in dimethylsulfoxide at room temperature for at least 2 hours. The mixture is then acidified with e.g. aqueous hydrochloric acid and then extracted with ethyl acetate and concentrated by evaporation.

Oxaprostaglandin F2a involves hydrolysis with aqueous acetic acid, concentration and purification by column chromatography.

IX -> oxaprostagland E2 requires treatment with Jones' reagent for approx. 20 minutes at -10 ° C to form another intermediate prior to the acid treatment and purification as above.

The novel reagent II is prepared by contacting an appropriate phosphonate such as dimethyl methyl phosphonate in a reaction inert solvent such as tetrahydrofuran and in a nitrogen atmosphere with an organolithium compound such as n-butyllithium. Then, a corresponding alkoxy ester such as methyl 4-methoxybutyrate is added and the product is purified by extraction in methylene chloride and concentrated.

From the literature cited, the natural prostaglandins are known to exert a spectrum of physiological activities. Numerous in vivo and in vitro tests have shown that the oxaprostaglandin analogs in question have the same physiological activities as the natural prostaglandins. These tests include a test for effect on isolated smooth muscle from guinea pig ileum and rat uterus, a test for efficacy on histamine-induced broncho-spasm in guinea pigs, a test for effects on canine blood pressure, a test for inducing diarrhea in mice. and a test for inducing abortion in prematurely pregnant rats.

The results of these different physiological tests are given in Table I below. It will be noted that these oxa-prostaglandin analogs not only have a fertility control effect that is quantitatively comparable to those of natural prostaglandins, but that they also have the benefit of tissue selectivity, especially 19-oxa-prostaglandin E2.

On the basis of the observed difference in rat uterus and guinea pig eum-per exercise with 19-oxa-prostaglandin E2, one would expect to have a reduction in the unpleasant gastrointestinal side effects encountered when 11 abrupt PGEg was used as an abortion inducer (Lancet , 536, 1971) · This important advantage has been abundantly confirmed by the fact that 19-oxa-prostaglandin E2 has now been found to be only 10% as effective as natural PGE2 in inducing diarrhea in mice, while equally effective as natural PGE2 for inducing abortion in the prematurely pregnant rat.

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The physiological responses observed in these tests are useful in determining the utility of the test substance in treating various natural and pathological conditions.

The following further tests comparing a number of oxaprostaglandin compounds of the invention with natural PGE2 and PGF2a show that the compounds of the invention have selective activities which make them useful as fertility control agents. Today, PGE2 and PGF2a are marketed for human use as a means of developing abortions in the third month. The tests used are as follows: Eel. Spasmogenic effect on isolated guinea pig uterus, expressed as relative potency (PGE2 / PGF2a = 100): a test for fertility control activity.

A2. Spasmogenic effect on isolated rat uterus, expressed as relative potency (PGE2 / FGF2a = 100): a test for fertility control activity.

B. Spasmogenic effect on isolated guinea pig ileum, expressed as relative potency (PGE2 / FGF2a = 100): a test for diarrhea, a common gastrointestinal side effect of prostaglandin diner.

C. Approximate% protection of guinea pigs against a toxic dose of histamine by aerosol administration of the agent in equimolar dose to 100 µg / ml PGE 2 (PGE 2 = 85%): a test for bronchodilator activity.

D. Threshold (in yug / kg in v.) For depressant effect on the blood pressure of anesthetized dogs (PGE2 = 0.1): a test for antihypertensive activity.

The results are given in the following Table II: 143498 9

TABEL_II

Connection Ex. Mp. All A2 B C D

--- 1 -—-- 1- 18-oxa-PGE 2 4 oil 11 3.3 3 1.0 19-oxa-PGE 2 1 55-56 ° C 10-20 10 1 19 1.0 19-oxa FGF2a 2 oil 15 10 2.5 19-oxa-vHomo-PGE2 3 58 ° C 33 10 38 0.4 19-oxa-u-homo-FGf, 2oc 3 oil 10 3

It can be seen from Table II, (1) that 18-oxa-PGE2, prepared in Example 4, is a more selective means of fertility control than PGE2 because of its 3x selectivity of spasmogenic side effect on the uterus rather than the ileum smooth muscle and its reduced bronchodilator and hypotensive activity; (2) that 19-oxa-PGE2, prepared in Example 1, is a more selective agent for fertility control than PGE2 because of its 10-20 times greater selectivity of spasmogenic effect on uterus rather than ileum smooth muscle and its reduced bronchodilator and hypotensive activity; (3) that 19-oxa-PGF2a, prepared in Example 2, is a more selective agent for fertility control than PGF2a because of its more than 4 times greater selectivity of spasmogenic effect on uterus rather than ileum smooth muscle; (4) that 19-oxa-u) -homo-PGE2 prepared in Example 3 is a more selective agent for fertility control than PGE2 because of its 3x selectivity of spasmogenic effect on uterus rather than ileum smooth muscle and reduced bronchodilator - and hypotensive activity; and (5) that 19-oxa-u-homo-PGF2a, prepared in Example 3, is a more selective agent for fertility control than PGF2a because of the 3-fold selectivity of spasmogenic effect on uterine rather than ileum smooth muscle.

The novel oxaprostaglandin compounds of the invention have more selective activity profiles than the corresponding naturally occurring prostaglandins and in many cases exhibit a longer duration of action. For example, if an intravaginal treatment for abortion induction is desired, a suitable medium is a tampon impregnated with 19-oxa-1 "-homo-"-pro staglandin-2α or lactose tablets with the same agent. a suitable dose should be about 100 mg, using 1 or 2 doses.

In cases where a mid-term abortion is needed, an effective agent would be a physiological saline solution of 19-oxa-PGE2 administered as an intravenous infusion. A suitable dosage could be from about 5 to about 100 pg / min, administered for a period of from about 2 to about 10 hours.

The novel oxaprostaglandin compounds of the invention can be used in a wide variety of pharmaceutical compositions containing the compound or a pharmaceutically acceptable salt thereof, and may be administered in the same way as natural prostaglandins by a variety of routes, such as intravenously, orally and topically, including as aerosol, intravaginally and intranasally. Pharmaceutically acceptable salts include salts of pharmaceutically acceptable bases such as alkali and alkaline earth metal bases, ammonia and amines.

To prepare any of the above dosage forms or any of the numerous other possible forms, various reaction-inert diluents, excipients or carriers may be used. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, vaseline, cholesterol and other known carriers for drugs. If desired, these pharmaceutical agents may contain adjuvants such as preservatives, wetting agents, stabilizers or other therapeutic agents such as antibiotics.

The following examples serve to illustrate the preparation of the oxaprostaglandin compounds of the invention.

EXAMPLE_1 A. A solution of 12.4 g (100 nmol) of dimethyl methyl phosphonate in 125 ml of dry tetrahydrofuran was cooled to -78 ° C in a dry nitrogen atmosphere. To the stirred phosphonate solution, 45 ml of 2.37 M n-butyllithium in hexane solution was added dropwise over 30 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° C, dropwise 6 was added. 6 g (50.0 mmol) of methyl 4-methoxybutyrate [prepared according to R. Huisgen and J. Reinertshafter, Am., 575, 197 (1952)] at a rate which kept the reaction temperature below -70 ° C (10 minutes). After 3 hours at -78 ° C, the reaction mixture was allowed to warm to ambient temperature and neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase extracted three times with 100 ml of methylene chloride each time, and the combined organic extracts dried over magnesium sulfate and concentrated (water jet pump) to a crude residue and distilled, b.p. 141 - 145 ° C / 1.7 - 0.6 mmHg to give 7.6 g (68%) of dimethyl 2-oxo-6-oxaheptylphosphonate.

Gas phase chromatography (using a 127 x 6 mm column containing 10% SE 30 on "Chromosorb1® P", particle size 0.149-0.177 mm, at 105 ° C) indicated a purity of> 99.9%. The NMR spectrum (CDCl3) showed: 0

A doublet centered at 3.78 <5 (J = 11.5 Hz, 6H) for (CH2 O) 2 -P-; a triplet centered at 3.37 δ (2H) for CH₂-O-CH₂-CH₂-; a singlet at 3.28 in (3H) for CH, -O-CHO-, -> d 0 0, a doublet centered at 3.14 4 (J = 23 Hz, 2H) for -C-CH5-P-; 0 * a triplet centered at 2.71 4 (2H) for -CH2-CH2-C- and a multiple 1.57 - 2.10 δ (2H) for -CH2-CH2-CH2.

B. The dimethyl 2-oxo-6-oxaheptyl phosphonate (1.68 g, 7.5 mmol) prepared in A in 125 mL of anhydrous ether was treated with 2.5 mL (5.9 mmol) of 2.37 M n butyllithium in n-hexane in a dry nitrogen atmosphere at room temperature. After 5 minutes of stirring, an additional 225 ml of anhydrous ether was added followed by 1.75 g (5.0 mmol) of 2- [3a-p-phenylbenzoyloxy-5oc-hydroxy-β-formylcyclopentan-Ια-yl] acetic acid eZ -lactone in one serving. After 30 minutes, the reaction mixture was reacted with 2.5 µl glacial acetic acid, diluted with 200 ml of anhydrous ether, washed twice with 200 ml of 10% hydrochloric acid, once with 200 ml of saturated aqueous sodium bicarbonate solution, once with 100 ml of water, dried over anhydrous magnesium sulfate. and evaporated to give 1.972 g (88%) of 2- [3α-β-phenyl-benzoyloxy-5α-hydroxy-2β- (3-oxo-7-oxa-trans-1-octen-1-yl) cyclo -pent-la-ylacetic acid- ^ lactone as an oil.

The infrared spectrum (CHCl 3) of the product exhibited absorption bands at 1770 cm -1 (strong), 1717 cm -1 (strong), 1675 cm -1 (medium) and 1630 cm -1 (medium) attributable to the carbonyl groups. The ultraviolet spectrum had a = 274 nm and a = 21,380 (ethanol solution). The NMR spectrum (CDCl3) showed a multiplet at 7.23 - 8.18 S (9H) for the p-biphenyl group, a duplicate of duplicates centered at 6.71 δ (1H, J = 7.16 Hz) and a duplicate centered at 6.27 δ (1H, J = 16 Hz) for the alkenic protons, a triplet at 3.30 i> (2H) for -C ^-C ^-O-CH₂, a singlet at 3.21 (3H) for -C ^-O-CH₂, and multiples at 4.90 - 5.50 ((2H), 2.21 - 3.07 S (8H) and 1.58 - 2.06 δ (2H) ) for the rest of the protons.

C. To a solution of 1972 mg (4.4 mmol) of 23α-p-phenylbenzoyloxy-5β-hydroxy-2β - (3-oxo-7-oxa-trans-1-octen-1-yl) cyclopentane L-acetone, prepared under B, in 15 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 4.0 ml of a 0.5 M zinc borohydride solution. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0 ° C and a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes, at which time 250 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker '' Analyzed Reagent, particle size 0.074 - 0.250 13, U $ 498 mm) using ether as eluent. minor polar impurities eluted fractions containing 450 mg of 2- [3a-p-phenylbenzoyloxy-5oc-hydroxy-2β- (3oc-hydroxy-7-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetic acid Lactone, 294 mg of 2- [3α-β-phenylbenzoyloxy-5α-hydroxy-2β- (3β-hydroxy-7-oxa-trans-1-octen-1-yl) cyclopent-1α-yl] acetic acid -lactone and 486 mg of the two mixed.

The infrared spectrum (CHCl3) of the first of these two compounds had strong carbonyl absorptions at 1770 and 1715 cm.

D. A heterogeneous mixture of 450 mg (1.0 mmol) of 2β-β-p-phenylbenzoyl-oxy-5eo-hydroxy-2β- (3x, -hydroxy-7-oxa-trans-1-octene-1 -yl) cyclopent-1-yl] acetic acid Clactone, prepared under C, 4.5 ml of absolute methanol and 140 mg of finely powdered anhydrous potassium carbonate was stirred at room temperature for 1 hour and then cooled to 0 ° C. solution was added 2.0 ml (2.0 mmol) of 1, QN aqueous hydrochloric acid. After stirring at 0 ° for an additional 10 minutes, 5 ml of water was added while forming methyl p-phenyl benzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (4 x 10 ml), the combined organic extracts washed with saturated sodium hydrogen carbonate (10 ml), dried over magnesium sulfate and concentrated to give 204 mg (76 g) viscous, oily 2- [3α, 5α-dihydroxy-2β- (3α-hydroxy-7-oxa-trans-1-octen-1-yl) -cyclopent-la-yl] acetic acid eZ ^ -lac t on.

The infrared spectrum (CHCl 3) exhibited strong absorption at - 1> Ί 1770 cm for the lactone carbonyl and mean absorption at 960 cm for the trans double bond.

E. To a solution of 192 mg (0.71 mmol) of 2- [3- [dihydroxy-2 (S- (3e.-hydroxy-7-oxa-trans-1-octen-yl) cyclopent-Lt-yl] acetic acid -) Phylactone, prepared under D, in 5 ml of anhydrous methylene chloride and 1 ml of 2,3-dihydropyran at 0 ° C in a dry nitrogen atmosphere was added 5 mg of p-toluenesulfonic acid monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether, the ether solution washed with saturated sodium bicarbonate (1 x 15 ml), then with saturated brine (1 x 15 ml), dried over magnesium sulfate and concentrated to give 310 mg (100%). ) 2- [5cc-hydroxy-3oc (tetrahydropyran-2-yloxy) -2β- (3a- [tetrahydropyran-2-yloxy] -7-oxa-trans-1-octen-1-yl) cyclopent-1 x-yl] -acetic acid lactone J ^.

The NMR spectrum (CDCl 3) showed a multiplet at 5.30 - 5.62 S (2H) for the alkenic protons, a singlet at 3.34 S (3H) for the methyl ether protons, and multiples at 4.36-5 , 18 in (4H), 3.22 - 4.24 ί (9H) and 1.18 - 2.92 £ (20H) for the remaining protons.

F. A solution of 310 mg (0.71 mmol) of 2- [5 * - hydroxy-3cL- (tetrahydropyran-2-yloxy) -2β- (3a- [tetrahydropyran-2-yloxy] -7-oxa) -trans-1-octen-1-yl) cyclopent-1β-yl} acetic acid β-lactone, prepared under E, in 5 ml of dry toluene was cooled to -78 ° C in a dry nitrogen atmosphere. To this cooled solution, 1.5 ml of 20% diisobutyl aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never rose above -65 ° C (15 minutes). After a further 45 minutes of stirring at -78 ° C, aqueous 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 of ether, washed with 50% sodium potassium tartrate solution (4 x 20 ml), dried over magnesium sulfate and concentrated to give 290 mg (93%) of 2- [5oc-hydroxy-3α (tetrahydropyran-2 yloxy) -2β- (3α- [t-ethrahydr o-pyran-2-yloxy] -7-oxa-trans-1-octen-1-yl) cyclopent-1-yl Jacetal dehydrohemiacetal.

G. To a solution of 870 mg (2.0 mmol) (4-oarboxy-n-butyl) -triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 ml of dry dimethyl sulfoxide was added 2.0 ml (4.4 mmol) of a 2 , 2 M solution of sodium methylsulfonylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 290 mg (0.66 mmol) of 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy] -7-oxa) -trans-1-octen-1-yl) cyclopent-1β-ylacetaldehyde-if-hemiacetal, prepared from tinder F, in 3.0 ml of dry dimethyl sulfoxide over 20 minutes. After a further 2 hours of stirring at room temperature, the reaction mixture was poured into water. The basic aqueous solution was washed twice with ethyl acetate (20 ml) and acidified to pH ca. 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml) and the combined organic extracts washed once with water (10 ml), dried over magnesium sulfate and evaporated to give 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, particle size 0.074 - 0.250 mm) using ethyl acetate as eluant. After removal of high Rf impurities, 225 mg (66%) of 9α-hydroxy-11cc, 15oc-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadienic acid were collected.

The NMR spectrum (CDCl3) showed a multiplet (variable) at 5.85 - 6.38 b (2H) for the -OH protons, a multiplet at 5.27 - 5.68 b (4H) for the alkenic protons, a multiplet at 4.52-4.84 in (2H) for the acetal protons, a singlet at 3.34 & (3H) for the methyl ether protons, and multiples at 3.25 - 4.35 b (9H) and 1 , 20 - 2.72 in (28H) for the remaining protons.

H. To a solution of 190 mg (0.356 mmol) of 9α-hydroxy-11 ', 15,11-bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid, prepared under G, in 5 ml of reagent pure acetone cooled to -10 ° C under a nitrogen atmosphere was added dropwise 0.143 ml (0.356 mmol) of Jones' reagent. After 20 minutes at -10 ° C, 0.140 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, at which time it was combined with 40 ml of ethyl acetate, washed with water (3x5 ml), dried over magnesium sulfate and concentrated, 174 mg of 9-oxo-11a, 15a-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid were obtained.

I. A solution of 174 mg (0.334 mmol) of 9-oxo-III-15β-bis-tetrahydro-pyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid, prepared under H, in 3.0 ml of a 65:35 acetic acid-water mixture was stirred under nitrogen at 40 ° C for 5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel ("Mallinck Root ^ CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate as eluant. After elution of minor polar impurities, the semisolid 9-οχο-11α, 15α-dihydroxy-19-oxa-cis-5-trans-13-prostadienic acid, which weighed 33 mg, was collected. This product is 19-oxa-prastaglandin E2, m.p. 58-59 ° C (ethyl acetate / cyclohexane).

16 143498

Analysis: Calculated: C 64.39 - Η 8.53 Found: C 64.30 - H 8.28.

[α] δ = -71.2 (C = 1.0, methanol).

The infrared spectrum of the product (CHCl3) showed a strong absorption at 1715 cm -1 for the carbonyl groups and mean absorption at 965 cm -1 for the trans double bond. The ultraviolet spectrum in methanol with added potassium hydroxide exhibited an λ = 278 nm and an e. = nidx max 28 000.

EKSEMPEL_2

A solution of 52 mg (0.10 mmol) of 9α-hydroxy-1115β-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid, prepared in Example 1-G , in 3.0 ml of a mixture of glacial acetic acid and water at a ratio of 65:35 was stirred under nitrogen at 40 ° C for 5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified on silica gel ("Mallinckrodt ^ CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate and then methanol as solvents. After eluting minor polar impurities, the oily 9oc, 11a, 15α-trihydroxy-cis-5-trans-13-prostadienic acid, weighing 15 mg, was collected. This product is 19-oxaprostaglandin F 2a EXAMPLE 3 A. A solution of 12.4 g (100 mmol) of dimethyl methyl phosphonate in 125 ml of dry tetrahydrofuran was cooled to -78 ° C in a dry nitrogen atmosphere. To the stirred phosphonate solution, 40 ml of 2.67 M n-butyllithium in hexane solution was added dropwise over 30 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° C, dropwise 8 was added. 0 g (50.0 mmol) of ethyl 4-ethoxybutyrate (prepared according to R. Huisgen and J. Reinertshafter, Ann., 575, 197 (1952)) at a rate that kept the reaction temperature below -70 ° C (10 minutes) ). After 3 hours at -78 ° C, the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase extracted with 100 ml portions of methylene chloride (three times), and the combined organic extracts dried over magnesium sulfate and concentrated (water jet pump) to a crude residue and distilled. , b.p. 130-132 ° C / 0.1 mmHg to give 7.4 g (62 #) of dimethyl 2-oxo-6-oxaoctyl phosphonate.

The NMR spectrum (CDCl1) showed D0 a doublet centered at 3.78b (J = 11.5 Hz, 6H) for (CH₂O₂-β-, a triplet centered at 3.28 <h (2H) for CH 2 -O-CH 2 -, a quartet at 3.43 h (2H) for CH 9 -O-CH 5 -, -O 0 a doubled centered at 3.14 ^ (J = 23 Hz, 2H) -C-CH 2 -P-, a triplet centered at 2.71 & (2H) for -CHg-CHg-C-, a multiplet 1.57 - 2.20 & (2H) for -CH2-CH2-CH2 and a triplet centered at 1 , B (3H) for CH-j-CHg-O-CH ,,.

B. 2.5 g (10.7 mmol) of dimethyl 2-oxo-6-oxaoctyl phosphonate prepared under A in 175 ml of anhydrous ether was treated with 5.0 ml (8.0 mmol) of 1.6 M n butyllithium in n-hexane in a dry nitrogen atmosphere at room temperature. After 5 minutes of stirring, an additional 350 ml of anhydrous ether was added followed by 2.5 g (7.2 mmol) of 2- [3α-p-phenylbenzoyloxy-5α-hydroxy-2β-formylcyclopentan-1-yl] -acetic acid - β-lactone in one serving. After 30 minutes, the reaction mixture was reacted with 5.0 ml of glacial acetic acid, diluted with 200 ml of anhydrous ether, washed with 200 ml of 10% hydrochloric acid (twice), 200 ml of saturated sodium bicarbonate solution (once), 100 ml of water (once), dried. over magnesium sulfate and evaporated to give 3.591 g (109%) of crude 2- [3cc-p-phenylbenzoyloxy-5oc-hydroxy-2β- (3-oxo-7-oxa-trans-1-nonen-1-yl) cyclopent-la-yl] acetic acid-r-lac ton as an oil.

The infrared spectrum (CHCl3) of the product exhibited absorption bands at 1776 cm -1 (strong), 1707 cm -1 (strong), 1665 cm -1 (medium) and 1620 cm -1 (medium) attributable to the carbonyl groups. The NMR spectrum (CDCl3) was consistent with the structure.

C. To a solution of 3491 mg (7.6 mmol) of crude 2- [3 <cp-phenylbenzoyl-oxy-5β-hydroxy-2β] - (3-oxo-7-oxa-trans-1 -nonone-1-yl) cyclopentyl-1-yl] -acetic acid-1-lactone, produced from tinder B, in 30 ml of dry 18 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 2.5 ml 0.5 M zinc borohydride solution.

After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0 ° C and a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 'minutes at which time 250 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker "Analyzed" Reagent, particle size 0.074-0.250 mm) using ether as eluant. After eluting minor polar impurities, fractions containing 705 mg of 2- [5a-p-phenylbenzoyloxy-5cc-hydroxy-2β- (3a-hydroxy-7-oxa-trans-1-nonen-1-yl) cyclopent-1a -yl] acetic acid / ilacone, a fraction containing 2- [3α-β-phenylbenzoyloxy-5α-hydroxy-2β- (3β-hydroxy-7-oxa-trans-1-nonen-1-yl) cyclopentyl la-yl] acetic acid-^ lactone and a fraction of the two mixed.

The infrared spectrum (CHCl3) of the first compound above 2-1 had strong carbonyl absorptions at 1770 and 1705 cm. The NMR spectrum (CDCl3) was consistent with the structure.

D. A heterogeneous mixture of 703 mg (1.5 mmol) of 2β-β-β-phenylbenz-oyloxy-5- (*) hydroxy-2β - (3d-hydroxy-7-oxa-trans-1-nonene) -l-yl) -cyclopent-1'-yl] -acetic acid Jjr-lactone, prepared under C, 7.0 ml of absolute methanol and 207 mg of finely powdered anhydrous potassium carbonate were stirred at room temperature for 1 hour and then cooled to 0 To the cooled solution was added 3.5 ml (3.0 mmol) of 1.0 N aqueous hydrochloric acid. After stirring at 0 ° C for a further 10 minutes, 7 ml of water was added while forming methyl p-phenylbenzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (4 x 10 ml), the combined organic extracts washed with saturated sodium bicarbonate (10 ml), dried over magnesium sulfate and concentrated to give 350 mg (85.5%). ) viscous oily 2- [3α, 5oc-dihydroxy-2β- (3α-hydroxy-7-oxa-trans-1-nonen-1-yl) cyclopent-1α-yl] acetic acid / β-lactone.

The infrared spectrum (CHCl 3) exhibited strong absorption at 1170 cm -1 for the lactone carbonyl and a mean absorption at 965 cm -1 for trans double bond.

E. To a solution of 350 mg (1.28 mmol) of 2- [3 <t, 5 <t- dihydroxy-2,2 -> - (3oL-hydroxy-7-oxa-trans-1-non-1-yl) ) oyelopent-1-yl] acetic acid β-lactone, prepared winner D, in 3.5 ml of anhydrous methylene chloride and 350 µl of 2,3-dihydropyran at 0 ° C in a dry nitrogen atmosphere was added 3 5 mg of p-toluenesulfonic acid. monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether, the ether solution washed with saturated sodium bicarbonate solution (1 x 15 ml) and then with saturated brine (1 x 15 ml), dried over magnesium sulfate and concentrated to give 590 mg (> 100%) 2- [5α-ΙΙη] -3α- (ΐβΐΓ3ΐητ (ΪΓορ3ΓΓηη-2 ^1οΧ5Γ) -2β- (3α- [tetrahydropyran-2-yloxy] 7-oxa-trans-1-nonen-1-yl) ) cyclopent-Ια-yl] acetic acid-X ^ lactone.

The NMR spectrum (CDCl3) showed a multiplet at 5.30 - 5.65 in (2H) for the alkenic protons, a quartet at 3.50 S (2H) for the ethyl ether protons, multiples at 4.35 - 5.18 h (4H), 3.22 - 4.24 S (8H) and 1.18 - 2.92 in (21H) and a triplet at 1.20 S (3H).

F. A solution of 575 mg (1.28 mmol) of crude 2- [5α-hydroxy-3α (tetrahydro-pyran-2-yloxy) -2β -) (3α- [tetishydropyran-2-yloxy] -7-oxa) -trans-1-nonen-1-yl) cyclopentyl-yl] -acetic acid - ^ - lactone, prepared under E, in 5.75 ml of dry toluene was cooled to -78 ° C in a dry nitrogen atmosphere. To this cooled solution, 1.8 ml of 20% diisobutyl aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never rose above -65 ° C (15 minutes). After an additional 1 hour stirring at -78 ° C, aqueous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 50 ml of ether, washed with 50% sodium potassium tartrate solution (4 x 10 ml), dried over magnesium sulfate and concentrated to give 458 mg (80%) of 2- [5α-hydroxy-3α (tetrahydropyran-2 yloxy) -2β- (3α- [tetrahydro-pyran-2-yloxy] -7-oxa-trans-1-nonen-1-yl) cyclopent-1-yl] ac-ethyl-dehyde-J-hemiacetal.

To a solution of 1330 mg (3.0 mmol) (4-carboxy-n-butyl)-triphenylphosphonium bromide in 6 ml of dry dimethyl sulfoxide in a dry nitrogen atmosphere was added 3.4 ml (6.8 mmol) of a 2 , 0 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 454 mg (1.0 mmol) of crude 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy) ] -7-oxa-trans-1-nonen-1-yl) cyclopent-1a-yl] -acetaldehyde-tf'-hemiacetal, prepared from tinder F, in 3.0 ml of dry dimethyl sulfoxide over 20 minutes. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (30 ml) and acidified to pH ca. 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 over magnesium sulfate and evaporated to a solid residue weighing 900 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker's Analyzed Reagent, particle size 0.074 - 0.250 mm) using ethyl acetate as eluant. After removal of high Rf impurities, 290 mg (54%) of 9α-hydroxy-11α, 15β-x-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans 13-m-homo-prostadienoic acid.

The NMR spectrum (CDCl3) showed a multiple (variable) at 6.2 - 6.6 b (2H) for the -OH protons, a multiple at 5.3 - 5.7 4 (4H) for the alkenic protons, a multiplet at 4.6 - 4.9 & (2H) for the acetal protons, a quartet at 3.5 4 (2H) for the ethyl ether protons, and multiples at 3.3 - 4.4 & (9H) and 1.0 - 2 , 6 b (31H) for the remaining protons.

H. To a solution of 290 mg (0.540 mmol) of 9β-hydroxy-11 *, 15 * - 'bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-w- homo-prostacetic acid, prepared under G, in 5.4 ml of reagent pure acetone cooled to -10 ° C under nitrogen was added dropwise 0.226 ml (0.600 mmol) 2.67 M Jones reagent. After 5 minutes at -10 ° C, 0.230 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, at which time it was combined with 30 ml of ethyl acetate, washed with water (3 x 5 ml), dried over magnesium sulfate, concentrated and chromatographed on silica gel (Baker, particle size 0.074 - 0.250 mm, CH 2 Cl 2 eluant) to give 180 mg of 9-oxo-11a, 15a-bis- (tetrahydropyran-2-yloxy) -19-oxa-cis- 5-trans-13 "fl * homo-prostadienoic acid.

I. A solution of 129 mg (0.240 mmol) of 9-οχο-κκ, 15 * -bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-uJ-homo-prostadioic acid, prepared under H, in 3.0 ml of a mixture of glacial acetic acid and water at 65:35 ratio was stirred under nitrogen at 40 ° C for 2.5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel ("Mallinckrodt © CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate as eluant. After eluting minor polar impurities, 9-oxo-11a, 15oc-dihydroxy-19-oxa-cis-5-trans-13-u> -homo-prostadioic acid, weighing 40 mg (mp 56-57 ° C), was collected. ). This product is 19-oxa-æ-homoprostaglan-din E2.

The ultraviolet spectrum in methanol with potassium hydroxide solution added showed a max = 278 nm and an emax = 25 700.

If 19-oxa-w? -Homoprostaglandin-F2 ^ is desired, the procedure set forth in Example 2 is followed using the product prepared under G above as the starting material.

EXAMPLE 4 A. A solution of 12.4 g (100 mmol) of dimethyl methyl phosphonate in 125 ml of dry tetrahydrofuran was cooled to -78 ° C in a dry nitrogen atmosphere. To the stirred phosphonate solution, 40 ml of 2.67 M n-butyllithium in hexane solution was added dropwise over 30 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° C, dropwise 7 was added. 6 g (50.0 mmol) of ethyl 3-ethoxypropionate at a rate that kept the reaction temperature below -70 ° C (10 minutes). After 3 hours at -78 ° C, the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase 22 was extracted with 100 ml portions of ether (3 times), the combined organic extracts were dried over magnesium sulfate and concentrated (water jet pump) to a crude residue and distilled, b.p. 107 - 114 ° C / 0.1 mmHg to give 5.6 g (50%) of dimethyl 2-oxo-5-oxaheptylpho sphonate.

The NMR spectrum (CDCl3) showed * 0 a doublet centered at 3 »79 £ (J = 11» 5 Hz, 6h) for (CH₂O₂-β-, a triplet centered at 3 »28 6 (2H) for CH2 -OC2 -C2 -> a quartet at 3 »436 (2H) for CH2 -O-CH« -, --- ^ 0 0 a doublet centered at 3 »14 in ) -C-CHg-P-, Π a triplet centered at 2.87 in (2H) for -CHg-C -CHg · B. 3.8 g (17.1 mmol) of dimethyl 2-oxo-5-oxaheptyl phosphonate, prepared under A, in 200 ml of anhydrous ether was treated with 4.8 ml (12 mmol) of 2.5 M n -butyllithium in n-hexane in a dry nitrogen atmosphere at room temperature After 5 minutes of stirring, an additional 400 ml of anhydrous ether was added followed by 4 g (11.4 mmol) of 2- [3cc-p-phenylbenzoyloxy-5-a-hydroxy-2β- formylcyclopentan-1-yl] -acetic acid r-lactone in one portion After 35 minutes the reaction mixture was reacted with 5.0 ml of glacial acetic acid, diluted with 200 ml of anhydrous ether, washed with 200 ml of 10% hydrochloric acid (2 times), 200 ml saturated sodium bicarbonate solution (1 time), 10 0 ml of water (1 time), dried over magnesium sulfate and evaporated to give 4.057 (80%) of crude 2- [3a-p-phenylbenzoyloxy-5a-hydroxy-2β- (3-oxo-6-oxa-trans). 1-octen-1-yl) cyclopent-1-yl] acetic acid Clacton as an oil.

The infrared spectrum (CHCl-j) exhibited absorption bands at 1770 cm -1 (strong), 1707 cm -1 (strong), 1767 cm -1 "(medium), and 1620 cm -1 can be attributed to the carbonyl groups.The NMR spectrum (CDCl3) was consistent with the structure.

C. To a solution of 4100 mg (9, -2 mmol) of crude 2- £ 3 <J (-p-phenylbenzoyl-oxy-5 <s (-hydroxy-2β- -l-octen-1-yl) cyclopent-Dc-23-acetic acid-β-l-lactone, prepared under B, 30 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at 0 ° C was added dropwise 4.5 After stirring at 0 ° C for one hour, a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes, at which time 200 ml of dry methylene chloride was added. and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker "Analyzed" Reagent, particle size 0.074 - 0.250 mm) using ether / ethyl acetate (5: 1) as eluent. minor polar impurities eluted fractions containing 778 mg of 2- [3oc-p-phenylbenzoyloxy-5α-hydroxy-2β- (3oc-hydroxy-6-oxa-trans-1-oc) tert-1-yl) cyclopent-1a-yl] acetic acid-3S-lactone (5), 2- [3β-phenyl-benzoyloxy-5oc-hydroxy-β - (3β-hydroxy-6-oxa-tanoic acid) 1-octene-1-yl) -cyclopent-loc-yl] -acetic acid} phylactone and 355 mg of the two mixed.

The infrared spectrum (CHCl3) of the first of the above fractions had strong carbonyl absorptions at 1775 and 1715 cm @ -1. The NMR spectrum (CDCl3) was consistent with the structure.

D. A heterogeneous mixture of 100 mg (2.24 mmol) of 2- [3t, -p-phenyl-benzoyloxy-5α-hydroxy-2β- (3 -l-yl) -cyclopent-11-yl-acetic acid-alpha-lactone, prepared under C, 10.0 ml of absolute methanol and 310 mg of finely powdered, anhydrous potassium carbonate was stirred at room temperature for 1 hour and then cooled at 0 ° C. To the cooled solution was added 10 ml (10 mmol) of 1.0 N hydrochloric acid. After stirring at 0 ° C for an additional 10 minutes, 10 ml of water was added while forming methyl p-phenylbenzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (2 x 100 ml), the combined organic extracts washed with saturated sodium bicarbonate (2 x 25 ml), dried over magnesium sulfate and concentrated to give 570 mg (94%) viscous, oily 2- (3α, 5α-dihydroxy-2β- (3α-hydroxy-6-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetic acid-2β-lactone.

The infrared spectrum (CHCl 3) showed a strong absorption at -170 cmA for the lactone carbonyl and mean absorption at 965 cm for the trans double bond.

E. To a solution of 570 mg (2.11 mmol) of 2-3,3 t, 5 µg of dihydroxy-2 £ - (3 ) cyclopent-1a: -yl} acetic acid - ^ - lactone, prepared under D, in 5.7 mg of anhydrous methylene chloride and 570 μΐ of 2,3-dihydropyran at 0 ° in a dry nitrogen atmosphere was added 5.7 mg p -toluensulfonsyre monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 200 ml of ether, the ether solution washed with saturated sodium bicarbonate (1x25 ml) and then with saturated brine (1 x 25 ml), dried over magnesium sulfate and concentrated to give 925 mg ( 100%) 2- [5α-hydroxy-3β- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy] -6-oxa-trans-1-octen-1-yl) cyclopentene -la-yl] acetic acid Clacton.

The NMR spectrum (CDCl3) showed a multiplet at 5.30 - 5.70 S (2H) for the alkenic protons, a quartet at 3.40 S (2H) for the ethyl ether protons, multiples at 4.35 - 5.18 & ( 4H), 3.18 - 4.32 pounds (8H) and 1.18 - 2.92 4 (25H) and a triplet at 1.10 & (3H).

F. A solution of 880 mg (2.01 mmol) of crude 2- 5'-hydroxy-3- (tetrahydropyran-2-yloxy) -2- (3- (3-tetrahydropyran-2-yloxy) -3- oxa-trans-1- octen-1-yl) cyclopent-1 (x.-yl) acetic acid-CLlactone, prepared under E, in 8.8 ml of dry toluene was cooled to -78 ° C in a dry nitrogen atmosphere. To this cooled solution, 3 ml of 20% diisobutyl aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never increased above -65 ° C (15 minutes). After a further 30 minutes of stirring at -78 ° C, aqueous methanol was added until The reaction mixture was combined with 100 ml of ether, washed with 50% sodium potassium tartrate solution (4 x 10 ml), dried over magnesium sulfate and concentrated to give 654 mg of 2- [5oc-hydroxy]. -3α- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydro-pyran-2-yloxy] -6-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetaldehyde tf'-hemiacetal.

To a solution of 2600 mg (6.0 mmol) (4-carboxy-n-toutyl) -triphenylphosphonium bromide in a dry nitrogen atmosphere in 6 ml of dry dimethyl sulfoxide was added 6.0 ml (12.0 mmol) of a 2 , 0 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 660 mg (1.5 mmol) of crude 2- [5oc-hydroxy-3oc- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy) ] -6-oxa-trans-1-octen-1-yl) cyclopent-1a-yl] -acetaldehyde-R 2 -hemiacetal, prepared under F, in 5.0 ml of dry dimethyl sulfoxide over 20 minutes. After a further 2 hours of stirring at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (100 ml) and acidified to pH ca. 3 with 10% hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts washed once with water (25 ml), dried over magnesium sulfate and evaporated to give 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, particle size 0.074 -0.250 mm) using ethyl acetate as eluant.

After removal of high R 2 value impurities, 550 mg (70%) of 9α-hydroxy-11α, 15oc-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid were collected. .

The NMR spectrum (CDCl3) showed a multiplet (variable) at 6.2 - 6.6 4 (2H) for the -OH protons, a multiple at 5 * 3 - 5.7 S (4H) for the alkenic protons, a multiplet at 4.6-4.9 pounds (2H) for the acetal protons, a quartet at 3.5 4 (2H) for the ethyl ether protons and multiples at 3.3-4.4 S (9H) and 1.0 2.6 4 (31H) for the remaining protons.

H. To a solution of 400 mg (0.765 mmol) of 9α-hydroxy-11α, 15α-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid, prepared under G, for 8 hours. ml of reagent pure acetone cooled to -10 ° C under nitrogen was added dropwise 0.338 ml (0.900 mmol) 2.67 M Jones' reagent. After 5 minutes at -10 ° C, 0.350 ml of 2-propanol was added and the reaction mixture was further stirred for 5 minutes, at which time it was combined with 60 ml of ethyl acetate, washed with water (3 x 5 ml), dried over magnesium sulfate and concentrated to give 280 mg of 9-ω-11α, 15α-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadienic acid.

I. A solution of 280 mg (0.240 mmol) of 9-oxo-lolo <15A-bis- (tetrahydro-dipyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid, prepared under H , in 4.0 ml of a mixture of glacial acetic acid and water at 65:35 ratio was stirred under nitrogen at 40 ° C for 2.5 hours and then concentrated by rotary evaporation. The resulting oil was purified by column chromatography on silica gel ("Mallinckrodi®CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate as. eluent. After elution of minor polar impurities, the oily 9-oο-11α, 15α-dihydroxy-18-oxa-cis-5-trans-13-prostadienic acid, which weighed 66 mg, was collected. This product is 18-oxaprostaglandin E2.

The ultraviolet spectrum in methanol with added potassium hydroxide solution exhibited an λ = = 278 nm and a ε = 23 800 - 25 600.

tucUC ωαΛ EXAMPLE 5

A solution of 75 mg (0.10 mmol) of 9β-hydroxy-11 / v, 15β-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid, prepared in Example 4-G, in 3.0 ml of a 65:35 acetic acid-water mixture was stirred under nitrogen at 40 ° C for 5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified on silica gel ("Mallinckrodt ^ CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate and then methanol as eluents. After eluting minor polar impurities, the oily 9a, 11a, 15a-trihydroxy-18-oxa-cis-5-trans-13-prostaglandic acid, which weighed 20 mg, was collected. This product is 18-oxaprostaglandin F2a.

EKSEMPEL_8

To a solution of 35 mg of 19-oxa-PGE 2, prepared in Example 1, in 7 ml of absolute methanol cooled in ice was added an ice-cooled solution of 105 mg of sodium borohydride in 12 ml of absolute methanol. The solution was stirred under nitrogen for 20 minutes at 0-5 ° C and then for 1.0 hour at room temperature. The reaction mixture was