CA1208634A - Fluoro prostacyclins - Google Patents

Abstract

ABSTRACT

Compounds of the formula I

wherein one of the double bonds indicated by broken lines is present in 4,5 or 5,6-position, R is hydrogen or lower alkyl, R1 is methyl, hydrogen or hydroxy;
R2 is hydrogen, methyl or fluoro; and R21 is hydrogen, fluoro, trifluoromethyl or methyl; with the proviso that when R21 is trifluoromethyl, R2 is hydrogen or methyl, their pharmaceutically acceptable salts, optical anti-podes or racemates are useful as anti-secretory agents, anti-hype-tensives, anti-ulcerogenic agents and blood platelet aggregation inhibiting agents. They can be prepared from compounds of the formula

Description

~LZ~

RAN 4303/ll The present invention relates to novel fluoro-prosta-cyclins, process for their preparation, intermediates therefor and pharmaceutical preparations containing them.

The novel fluoro-prostacyclins of the present invention 10 have the general formula ,5~
`4 ~ (CH~)2cooR
6 ~ p .._ ~
¦ R
-l ~ CH=CH~C_ I ~ (CH2)~H3 ~ 21 wherein one of the double bonds indicated by broken lines is present in ~,5 or S,6 position; R is hydrogen or lower alkyl Rl is methyl, hydrogen, or hydroxy;
R2 is hydrogen, methyl or fluoro; and R2l is hydrogen, fluoro, trifluoromethyl or methyl; with the proviso that when R2l is trifluoromethyl, R2 is hydrogen or methyl.
The invention also relates to their pharmaceutically acceptable salts, optical antipodes or racemates.
A preferred aspect of the present invention is concerned with compounds of the formula Grn/25.l.82 '~

3~

o ~,H2-CH2-CH2-C-OR
O = F
A

CH=CH^C~--C-CH2-CH2-CH2-C1~3 -~l OH R

wherein R, Rl, R2 and R2l are as above.

In another aspect, the present invention is concerned with compounds of the formula O
H CH_CH-CH2 CH2 C-OR
~ F l-B
- ~ R2l r~ I .
H-cH-f-c~2-c~2 CH2 C 3 Rl OH R.

~5 wherein R, Rl, R2 and R2l are as above.

As used throughout this application, the term "lower alkyl" includes both straight chain and branched chain 30 alkyl groups having from l to 7 carbon atoms such as methyl and ethylO As also used herein, the ~erm "lower alkanoic acids" comprehends an alkanoic acid of l to 7 carbon atoms such as formic acid and acetic acid. As further used herein, the term "halogen" or "halo", unless otherwise stated, 35 comprehends fluorine, chlorine, bromine and iodine. Alkali metal includes all alkali metals such as lithium, sodium and potassium.

3~

In the process of this invention, all compounds having one or more asymmetrlc carbon atoms can be produced as racemic mixtures. These racemic mixtures which are obtained can be resolved at the appropriate steps in the process of this lnventlon by methods well known ln the art whereupon subse~uent products may be obtained as the corresponding optically pure enantiomers. On the other hand, the claimed optically active enantlomer or racemates of formula I can be produced depending upon the optical form of the compound 10 of formula II utllized as a starting material.

- In the pictorial representation o~ the compounds given throughout this application, a thickened taper line ( ~ ) indicates a substituent which is in the beta-orienta-15 tion (above ~he plane of the molecule), a dotted line (~
indicates a substituent which is in the alpha-orientation (below the plane of the molecule) and a wavy line (rv~) indicates a substituent which is in either the alpha- or beta-orientation or mixtures of these isomers. It is to be 20 understood that the pictorial representations of the compounds given throughout the specification are set forth for conveniance and are to be construed as inclusive of other forms including enantiomers and racemates and are not to be construed as limited to the particular form shown.
As also used herein, the term "aryl" signifies mono-nuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more positions with a lower alkylenedioxy, nitro, halo, a 30 lower alkyl or a lower alkoxy substituent, and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl, azulyl, etc., which can be unsubstituted or substituted with one or more of the aforementioned groups. The preferred aryl groups are the substituted and unsubstituted mononuclear 35 aryl groups, particularly phenyl.

The term "ether protecting group removable by acid catalyzed cleavage" designates any ether which, upon acid 6~

catalyzed cleavage yields the hydroxy group. A suitable ether protecting group is, for example, the tetrahydro-pyranyl ether, or 4-methyl-5,6-dihydro-2H-pyranyl ether.
Others are arylmethyl ethers such as benzyl, benzylhydryl, or trityl ethers or alpha-lower alkoxy lower alkyl ether, for example, methoxymethyl or allylic ethers, or tritlower alkyl)silyl ethers such as trimethyl silyl ether or di-methyl-tert-butyl silyl ethers. The preferred ethers which are removed by acid catalyzed cleavage are t-butyl and 10 tetrahydropyranyl and the tri(lower alkyl)silyl ethers, particularly dimethyl-tert-butyl ethers. Acid catalyzed cleavage is carried out by treatment with a strong organic or inorganic acid. Among the preferred inorganic acids are the mineral acids such as sulfuric acid, hydrohalic 15 acid, etc. Among the preferred organic acids are lower alkanoic acids such as acetic acid, para-toluene sulfonic acid, etc. The acid catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent medium. ~here an organic acid is utilized, the organic acid can be the 20 solvent medium. In the case of t-butyl, an organic acid is generally utilized with the acid forming the solvent medium. In the case of tetrahydropyranyl ethers, the cleavage is generally carried out in an aqueous medium.
In carrying out this reaction, temperature and pressure are 25 not critical and ~his reaction can be carried out at room temperature and atmospheric pressure.

Among the preferred compounds of formula I --are those compounds where the 7-fluoro substituent is in 30 the beta configuration. Among the 7-beta fluoro compounds, the following are preferred:

3~

.

CH-CtI2 C~2 2 F I-Ai CH=CH-CH-C C~I2-cH2-cH2-cH3 0~1 ~5H CH 3 ,~H-CH2-CH2~CH2-~-O~ I-Aii CH=CH-CH-CH-CE~2-CH2-CEI"~CH3 OH ~H
o 52'~CH2-CH2-CH2~ C)R
---- CH I`-Aiii ~=CH-C~C--CH2-C~a-CH2-CH3 =
CH3 OE~ CH3 .. O

. I I-Aiiii ~LCH=CH CH-fIl-c~2-cH2-cH2-c~3 ;~ OH F
~,H3 When R is lower alkyl in the compound of formulae I-Ai, I Aii, I-Aiii and I-Aiiii, R is preferably methyl or ethyl.

The co~pounds of formula I are prepared from a compound of formula , ~---_ R2 1 11 CH=CH-CH-C-CH2-CH2-CH2-CH3 wherein R , R and R are as above, or optical antipodes or racemates thereof, via the inter-mediates IV to.XII:

Q _ ~ 1 ~æ CH=cH-cH-c-cH2-cH~-cH2-cH3 RlR5 ~ 412 /--R21 y -11 ~ C~-CH-C~ -C -CH2-CH2 CH~ 3 EE: oR4 R2 .= _ 35 ~--1 R2 1 VI

CH=CH-CH-l -CH~ CH2 2 3 ,. .

i3~

O

F
_ , YII

_1 ~ CH=cH-cH-l -CE~-CH2 CH2 3 R OH R
OEI

r-l R2 1 VIII

CH2 CH2-cH2~cH3 ~0 CH=CH-CH2-CH2-CH2-COOH IX

Rll CH=CH-ICH C--CH2-CH~ CH2 C 3 HO,~ -CH=CH-CH2-CH2-CH~-cooR6 Rll ~ CH=CH-ICH -C--CH -CE~ H -CH
X O
H~,< CH-CH2~CH -CH -C-OR6 --~ F

~T R21 X~
- ~ CH=C~-CH -C -CH2 CH2 2 3 8~

CH-C~2-CH2-CH2-~-OR6 ~ F
a R2 l XII
CH=CH-_H - IC -C}12-CH2-CH2-CH3 Ri OH R

~CH~-CH2-CH2-C-OR6 ~ = F
- -- XIII
~ R.21 \ ~ ~CH=CH-CH-C -CH2-CH2-CH2-CH3 R OH R

H ~ CH-c~l-cH2-cH2-c-oRB
.~ F

~_ R2 1 XIV
CH=CH -CH-C -CH -CH -CH -CH
R~ H I 2 ~,-CH2~CH~-C~ -OH
F

CH=CH -CH -C -CH -CH -CH -CH

H ~",--~CH-CH-CH -~-OH
(~ _ F
-~21 XYI
C~--CEI -CH-C -C~2-C~2-C~2 C 3 R~ H I 2 .

:~2~3~
g wherein R, Rl, R and R are as above, R l is hydro-gen, methyl or OR ; -OR form an ether protecting group ~emovable by an acid catalyzed cleavage; R6 is lower alkyl; X is halogen; and R is tri(lower alkyl)silyl.

The compound of formula II is converted to the com-pound of formula IV by conventional etherification in order to protect any ~ree hydroxy groups in the compound of 10 formula II. Where R is hydroxy in the compound of formula II, this etherification converts the hydroxy group to the protected ether in the compound of formula IV. The pre-ferred ethers for use in this reaction are tetrahydropyranyl and dimethyl-t-butyl silyl ether. In carrying out this 15 reaction, any conventional method of etherifying the compound of formula II can be utilized in forming the compound of formula IV. When a tri(lower alkyl)silyl ether is desired, a tri~lower alkyl)chlorosilane is utilized as the etherifying agent in the presence of an organic base 20 such as imidazol or pyridine. Any conventional organic amine base can be utilized in carrying out this reaction.

The compound of formula IV is converted to the com-pound of formula V by first enolizing the compound of 25 formula IV and then treating the compound of formula IV
with a trialkyl halosilane. Any conventional method of enolizing can be utilized to carry out this reaction. Among the preferred methods is by treating the compound of formula IV with a non~aqueous alkali metal base.
30 The preferred base for use in this reaction is lithium diisopropyl amide or sodium hexamethyldisilazane. In carrying out the reaction utilizing the non-aqueous alkali metal ba~e, temperaturas of -70 ~o -30 are generally pre-ferred. Genexally, this reaction is carried out in an inert organic solvent. Any con~entional inert organic sol-vent which is a liquid at the aforementioned temperatures can be utilized. Among the preferred solvents is tetra-hydrofuran. The enolate of the compound of formula IV inthe form of its alkali metal salt is converted to the compound of formula V by treatlng the compound of formula V with a trlalkyl halosilane, preferably trimethylchloro-silane. Generally, this reaction is carried out at thesame temperatures and in the same solvent utilized to form the enolate.

The compound of formula V is converted to the compound ~0 of formula VI by treating the compound of formula V with a fluorinating agent. Any conventional fluorinating agent can be utilized in carrying out this reaction. Among the preferred fluorinating agents are xenon difluoride, fluorine gas, etc. Generally, this reaction is carried out 15 in the presence of an inert organic solvent. Any conventio-nal inert organic solvent can be utilized in carrying out this reaction. Among the preferred solvents are halogenated hydrocarbons such as methylene chloride, carbon tetra-chloride, etc. In carrying out this reaction, temperature 20 and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure.
While room temperature can be utilized, it is preferred to carry out this reaction at low temperatures, i.e. from -10C to +10C.
In converting the compound of formula V to the compound of formula VI, the compound of formulaVI is produced as a mixture of the following compounds:

~
~ F
. _ 2l VI-A

ll CH=CH-CH -C ~C~2-CH2-CH2-CH3 R = 4 2 ~ R R
and 863~L

~ F
CCH_CH_CH_C_CH -CH -CH -CH VI-B
-11 oR4 R2 R

wherein R l, R and R are as above.

The compounds of formulae VI-A and VI-B can be separated by conventional methods such as chromatography.
On the o-ther hand, the compound of formula VI as a mixture of the compounds of formulae VI-A and VI-B can be utilized throughout the rest of the reaction or, if desired, separa-15 ted at some later state in the reaction scheme to producethe compo~lnd of formulae I having the desired fluoro orientation at the 7-position. If the compound of formula VI is separ~ted into the compound of formulae VI-A and VI-B, the same configuration of the fluorine atom is 20 carried out throughout the rest of the reaction. Therefore, if the compounds of formulae I wherein the fluorine atom is at the 7-beta position, are desired, the compound of formula VI-A is utilized in the rest of the reaction scheme producing compounds of the formulae VII through XVI
25 wherein the fluorine atom set forth in these formulae is in the beta position. If the compounds of I are desired wherein the fluorine is in the 7-alpha position, then the compound of formula VI-B is utilized in the reaction scheme to produce the compounds of ~ormulae VII through 30 XVI wherein the fluorine atom shown in these formulae is in the alpha position.

On the other hand, the compound of formula VI can be utillzed without separating it into the compounds of 35 formulae VI-A and VI-B. In this manner, the compounds of formulae I wherein the fluorine is in both of the alpha and beta positions is produced via intermediates of the ~L2~

formulae VII through XVI having the fluoro group in the same position as shown.

In converting the compound of formula II to the com-pound of formula VI, it is generalLy preferred to utilizethe tri(lower alkyl)silyl ethers as the hydroxy protecting group. In the conversion of the compounds of formula VI to the compounds of formulae I it is generally preferred to protect one or more of the hydroxy groups with a tetra-10 hydropyranyl ether. On the other hand, the silyl ethersor any other conventional ethers can be utilized in the rest of this process. However, in accordance with the pre-ferred embodiment, the silyl ethers of formula VI are hydrolyzed to produce the compound of formula VII which is then reetherified to produce the compound of formula VI
wherein the ether group is tetrahydropyranyl. Any conven-tional method of hydrolyzing ethers can be utilized to carry out the conversion of the compounds of formula VI
to the compounds of formula VII and any conventional 20 method of etherification can be utilized to carry out the reconversion of the compounds of formula VII to the com-pounds of formula VI. With tetrahydropyranyl as the protec-ting group in the compound of formula VI, there is no need to hydrolyze the compound of formula VI to the compound of 25 formula VII since the compound of formula VIII can be pro-duced directly from the compound of formula VI.

The compound of ~ormula VII is converted to the com~
pound of formula VIII by treating the compound of formula 30 VII with a reducing agent. In carrying out this reaction, any conventional reducing agent which will selectively reduce a keto-group to a hydroxy-group can be utilized.
Preferred reducing agents are the hydrides, particularly the aluminum hydrides such as alkali metal aluminum hydride, 35 and the borohydrides such as alkali metal borohydrides, with diisobutyl aluminum hydride being particularly pre-ferred. Also, this reaction can be carried out utilizing di(branched chain lower alkyl)boranes such as bis(3-methyl-"~

~2~8~i3~L
_ 13 -

2-butyl)borane. In carrying out this reaction, temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures.
Generally, it is preferred to carry out this reaction at a temperature of from -80C to the reflux temperature of the reaction mixture. This reduction reaction can be carried out in the presence of an inert organic solvent.
Any conventional inert organic solvents can be utilized in carrying out this reaction. Among the preferred sol-vents are dimethoxy ethylene glycol, and the ethers such as tetrahydrofuran, diethyl ether and dioxane.

The compound of formula IX is obtained from the com-15 pound of formula VIII by reacting the compound of formula VIII with phosphonium salts of the formula:
Rb O

R ~ P () CH2 C ~ CH2 CH2 ~ -OH
lc XX-~
y(~) wherein R , R , R is aryl or di(lower alkyl)amino;
and Y is halogen, via a conventional Wittig type reaction. Any of the con-25 ventional conditions in Wittig reactions can be utilizedin carrying out this reaction.

The compound of formula IX can be converted to a compound of the formula X by esterification with diazo-30 methane or a reactive derivative of a lower alkanol such asa lower alkyl halide. Any conventional conditions utili-zing in these esterifying reactions can be utilized to form the compound of formula X from the compound of formula IX.
The compound of formula X is converted to the compound of formula XI by treating the compound of formula X with a halogenating agent. Among the preferred halogenating agents ~Z~863~

are included N-halosuccinimides, particularly N-iodosuccini-mld~. Generally, this reaction is carried out in the presence of a polar solvent such as acetonitrile and halo-genated hydrocarbons such as methylene chloride, ethylene chloride, etc. In fact, any conventional polar organic solvent can be utilized. In carrying out this reaction, temperatures of from 0 to 35C can be utilized. Generally, it is preferred to carry out this reaction at room temperature.

The co~pound of formula XI is converted to the com-pound of formula XII by ether hydrolysis. Any conventional method of ether hydrolysis can be utilized to carry out this reaction. Generally, it is preferred to utilize mild acid hydrolysis such as aqueous acetic acid.

In the next step, the compound of formula XII is treated with a dehydrohalogenating agent to produce the compounds of formulae XIII and XIV in admixture. In 20 carrying out this reaction, any conventional dehydrohalo-genating agent can be utilized. Among the preferred dehydrohalogenating agents are the diazabicycloalkanes or alkenes such as 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane. Furthermore, any other 25 conventional organic base utilized for dehydrohalogenation can be utilized in carrying out this reaction. This reac-tion produces the compounds of formula XIII and the com-pounds of formula XIV in admixture. The compounds of formula XIII can be separated from the compounds of 30 formula XIV by any conventional procedure such as chromato-graphy.

The compound of formula XIII is converted to the com-pound of formula XV and the compound of formula XIV is 35 converted to the compound of formula XVI by hydrolysis.
Any conventional method of ester hydrolysis can be utilized in carrying out these reactions. Among the preferred method of ester hydrolysis is either treating the compound of 36~

formula XIII or the compound of formula XIV with a alkali metal hydroxide. Among the preferred alkali metal hydroxides for use in this reaction are sodium and potassium hydroxides.

In the practice of this invention, any pharmaceuti-cally acceptable basic salts of the compound of formula I
where R is hydrogen can be utilized. Among the preferred pharmaceutically acceptable basic salts are included the alkali metal salts such as lithium, sodium, and potassium, 10 with sodium being especially preferredO Other salts which are also preferred are the alkaline earth metal salts such as calcium and magnesium, amine salts such as the lower alkyl amines, e.g. ethylamlne and the hydroxy-substituted lower alkyl amine salts and tris(hydroxymethyl)amino-15 methane. Also preferred are the ammonium salts. Among theother salts are dibenzylamine, monoalkylamines or dialkyl-amine and salts with amino acids (i.e. salts with arginine and glycine).

Among the preferred compounds of this invention are compounds of the formula XIII and XV where R1 and R2 are both hydrogen.

The compounds of formula I their pharmaceutically 25 acceptable salts as well as optical antipodes and race-mates thereof are useful as anti-secretory agents, anti-hypertensives, anti-ulcerogenic agents, and for combating gastro-hyperacidity and for anti-blood platelet aggregating agents.
Tha~ the prostacyclins of formula I of this invention are active as anti-blood platelet aggregating agents can be seen from the administration of (5Z,7~,9a,11~,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-35 5,13-dien-1-oic acid methyl ester by the folLowing test.

30 ml of blood was drawn from the jugular vein of a conscious beagle using two 15 ml Vacutainer tubes, with ~2~8~

no additive, connected to a 20 g 1 inch multiple sample needle. The blood was immediately transferred to a 50 ml conicalplastic centri~uge tube containing 3 ml of 3.8%
sodium citrate (3.8 grams of sodium citrate crystal, Na3C6H5O7.2H2O, in 100 ml of distilled water), capped and gently mixed. The citrated blood was centrifuged at 160 g for 15 minutes at 20C. The platelet rich plasma (PRP) was carefully withdrawn with a pipette, without disturbing the buffy coat and erythrocyte layers. The PRP was placed 10 in 16 x 125 mm plastic tubes, capped and stored at room temperature 19-21~C. PRP preparations showiny a tinge of redness, indicative of hemolysis, were discarded. The remaining blood, after the removal of PRP, was recentri-fuged at higher speed, 900 g for 10 minutes, to yield 15 platelet poor plasma (PPP). The ~RP was used immediately and the aggregation study completed within three hours after preparation.

Platelet aggregation was measured with a Payton dual 20 channel aggregation module connected to a dual pen recorder for the continuous recording of the increase in light transmission due to clumping of platelets. The 0-100%
transmission scale was set with PRP (0% and PPP (100%).
The temperature was set at 37 and the stirring speed at 25 900 xpm. 0.45 ml of PRP was added to a cuvette containing a teflon coated stirring bar and prewarmed at 37 in a water bath. 5 ~l of various concentra~ions of (5Z,7~, 9a, -lla, 13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta 5,13-dien-1-oic acid methyl ester, diluted 30 from a stock solution of 5 x 10 M in DMSO (dimethylsul-foxide) with phosphate buffered saline containing 1 mg/ml of bovine serum albumin, fraction V, was added and stirred for 1 minute. The inducer of aggreagation, arachidonic acid, at a concentration which will cause 50-70% aggrega-36 tion after 5 minutes, was then added in 50 ~l of solution.The % inhibition, set forth in the following Table, was calculated from the ratio of the % aggregation with ( 5Z, 5~, 9a, lla,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-~38~

16,16-dimethyl-prosta-5,13-dien-1-oic acid methyl ester over that with the vehicle x 100.

Concentration of (5Z,7~,9a,11~,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oic acid methyl ester % Inhibition 1 x 10 M 14.2 1o~l?,M 20.8 1 10-12 71.4 1 10-11 57.8 1 x 10 M 20.8 15 The preparation of phosphate buffered saline and arachidonic acid solution used above is as follows:
Phosphate buffered saline (PBS) was prepared by adding 1 mM solution of sodium phosphate aqueous buffer, pH 7.4 to 0.85% by weight/volume of an aqueous sodium chloride ~ solution. Arachidonic acid solution was prepared as follows:
A stock solution of 10 mg per ml in absolute ETOH was prepared and stored in freezer. To make a 10 mM solution, 0.3 ml of the stock solution was evaporated to near dryness under nitxogen and redissolved in 0.75 ml of 0.02 NH40H
(freshly prepared) and 0.2 ml of PBS. Further dilutions of arachidonic acid were made with NH40H and PBS mixture.

The compounds of formula I or their pharmaceutically acceptable salts can be used in a variety of pharmaceuti-30 cal preparations. In these preparations, the new compoundsare administerable in the form of tablets, pills, powders, capsules, injectables, solutions, suppositorien, emul-sions, dispersions, and in other suitable forms. The pharmaceutical preparations which contain the compounds of 35 formula I are conveniently formed by admixing with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical of pharma-ceutically acceptable carriers are, for example, water, ~2~34 gelati,n, lac~ose, starches, magnesium stearate, talc, vegetable oils, polyaIkylene glycols, petroleum jelly and other conventionally employed pharmaceutically acceptable carriers. The pharmaceutical prepara-tions may also contain non-toxic auxiliary substances SUCil as emulsifying, preserving and wetting agents and the like, as for example, sorbitan monolaurate, triethanol amine oleate, polyoxy-ethylene sorbitan, dioctyl sodium sulfosuccinate and the like.
The daily dose administered for the compounds will, of course, vary with the particular novel compound employed because of the very potency of the compounds, the chosen route of administration and the size of the recipient. The 15 dosage administered is not subject to definite bounds but it will usually be in effective amounts of the pharma-cologically function of the prostacyclin. Representative of a typical method for administering the prostacyclin compounds of formula I is by oral administration. By this 20 route, the prostacyclins of formula I can be administered at a dosage of 0.1 micrograms to 0.30 micrograms per day per kilogranl of body weight.

The following Examples are illustrative but not 25 limitative of the inYention. In the Examples, the ether utilized was diethyl ether. A11 temperatures are in degrees Centigrade. The petroleum ether utilized in the Examples had a boiling point of from 35 to 60C. In the Examples, "h" indicates hours.

3~

36~
_ 19 --Example 1 [3aR-[3aa,4a(1E,3R*),5~,6aa]]-Hexahydro-5-[[(1,1-dimethyl-ethyl)dimethylsilyl]oxy]-4-[[[3 (l,l-dimethylethyl)-dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta-[b]furan-2-one 502.2 mg (1.69 mmol) of [3aR-[3aa,4a(1E,3R*),5~,6aa]]-hexahydro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one, was dissolved in 15 ml of dimethylformamide (reagent grade, dried over 3A molecular sieves) under a positive argon pressure. 1.045 g (6.93 mmol = 4.09 eq.) of t-butyldimethylchlorosilane (dist.
be~ore use) and 587.6 mg (8.63 mmol = 5.09 eq.) of imidazole (reagent grade) we~e!a~ded. The resulting mixture was stirred at room temperature for 18 h, poured lnto 60 ml ice cold 0.5 N aqueous HCl and extracted three times with 60 ml of diethylether. The extracts were washed with 60 ml of a mixture of sat. aqueous NaHCO3/H2O/brine =
20 1:1:2 ~ollowed by washing with 60 ml brine. The extracts were combined, dried over MgSO4 and concentrated at reduced pressure. 1.25 g of a white semi-solid remained.
The crude product was chromatographed on a 75 g silica gel column with 10% by volume ether/90% by volume petroleum 25 ether (~irst llt) ~ollowed by 20% by volume ether/80% by volume petroleum ether. 857.1 mg (1.63 mmol, 96.4F) of [3aR-[3aa,4a(1E,3R*),5~,6aa]]-hexahydro-5-[[(1,1-dimethyl-ethyl)dimethylsilyl]oxy]-4-[[[3-tl,l-dimethylethyl)-dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta-30 [b]~uran-2-one as a white amorphous solid was obtained;
mp 67-68.

Example 2 35 [3aR-[3aa,4a(lE,3R*),5~,6a~]]-4,5,6,6a-Te-trahydro-5-[[1,1-dimethylethyl)dimethylsilyl3Oxy]-4-[[[3-(1,1-dimethyl-ethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octeny]]-2-(tri-met~ylsilyl)oxy 3aH-cyclopenta[b]furan .

570 ~l (4.07 mmol) of dilsopropylamine (dist. from CaH2) was dissolved in 15 ml of tetrahydrofuran (freshly dist. from LAH). The mixture was cooled to +3C under a positive argon pressure. 2.5 ml (3.75 mmol) o~ 1.5 N n-butyllithlum ln hexane was added dropwise at +3C. Afterstirriny at +3~C for 5 min, the mixture was cooled to ~40C wlth a dry ice/acetone bath. 1.757 g (3O35 mmol) of [3aR-[3aa,4a(lE,3*R),5~,6aa]]-hexahydro-5-[[(1,1-dime-thylethyl)dimethylsilyl]oy]-4-[[[3-(1,1-dlmethylethyl)-10 dimethylsllyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta-[b]furan-2-one dlssolved in 6 ml THF was added ropwise to the lithium diisopropylamide solutlon at -40C. After stirring at -40C for an additional 5 min, 570 ~l (4.49 mmol) of trimethylchlorosilane (dist.) was added rapidly.
15 Two min after the addition, the cooling bath was removed and the mixture was allowed to warm to ~15C over a 20 min period. The solvent was removed under vacuum (ca. 0.2 MMHG) at or below room temperature and the residue was dried at high vacuum for lS min. 10 ml of ether (freshly 20 filtered through aluminum oxide, activity I) was added under argon and the mixture was filtered througj a sintered g~ass funnel. The white residue was washed three times with 3 ml of ether. The slightly yellow filtrate was con-centrated under vacuum and the oily residue was dried at 25 high vacuum (room temperature) for 1 h producing [3aR- -~3aa,4a(1E,3*R),5~,6aa]]-4,5,6,6a-tetrahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[C3-(1,1-dimethyl-ethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2-(tri-methylsilyl)oxy 3aH-cyclopenta[b]furan.
Example 3 [3S-[3a,3aa,4a(lE,3*R),5~,6aa]]-Hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethyl-35 ethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclo-penta[b]furan-2-one 3~

The compound [3aR-[3aa,4a(1E,3*R),5~,6aa]]-4,5,6,6a-tetrahydro-5-[[1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dlmethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2-(trimethylsllyl)oxy-3aH-cyclopenta[b]furan was dissolved in 15 ml of methylene chloride (freshly filtered through aluminum oxide, activity I) under argon. The mixture was cooled to +2C with an ice/water bath. 680 mg (6.8 mmol) o~ potassium bicarbonate (dried at high vacuum at 100 over P2O5 for 3 h) followed by 632.9 ~g (3.73 mmol) lO of xenon difluoride were added under stirring. An immediate reaction ensued as judged by the vigorous gas evolution in the flrst 30 secO after the addition of XeF2. The mixture was stirred at +2C for 20 min, poured into 150 ml of ice cold water and extracted three times with 150 ml of methy-15 lene chloride. The extracts were washed twice with 150 mlof brine, combined, dried over MgSO4 and concentrated at reduced pressure. The residue was dried at high vacuum for 18 h leaving 1.92 g of a yellowish oil.

The crude product was chromatographed on 200 g of silica gel (230-400 mesh) using the flash chromatography technique. 5% by volume ethyl ace~ate/95% by volume petroleum ether (1 lt) followed by 10% ethyl acetat~/
petroleum ether were used as eluting solvents. The follo-25 wing products were obtained in order of elution: 1.06 g(1.95 mmol) 58% of [3S-C3a,3aa,4a(lE,3*R),5~,6aa]]-hexa-hydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-

4-[[[3-(1,1-dimethylethyl)dimethylsilyl]-oxy]~4,4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-~-one; white needles 30 formed on standing, m.p. 49-51~ 165.2 mg (0.31S mmol) 9.4% of [3aR-[3aa,4a(1E,3*R),5~,6aa]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)-dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta-[b]furan-2-one, starting material; and 98.9 mg (0~182 mmol) 35 S.4% of 3R-[3~,3aa,4a(1~,3*R),5~,6aa]-hexahydro-3-fluoro-

5-[[(1,1-dimethylethyl)dimethylsilyl~oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]-oxy]~4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one; amorphous white solid;

39~

m.p. 83-85.

Example 4 [3S [3a~3aa~4a(lE~3*R)~5~6aa]]-Hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta-[b3furan-2-one 1.597 g (2.94 mmol) of the fluoro lactone [3S-[*a,-3aa~a(lE~3*R)~5~6aa]-hexahydro-3-fluoro-5-[[(l~l-dimeth ethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)di-methylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H~cyclopenta[b]-furan-2-one was dissolved in 60 ml of acetic acid (reagent grade) and the mixture was warmed to 55C under a positive argon pressure. 6 ml of water was added with stirring at 55C. After 7 h, an additional 4 ml of water was added and stlrring at 55C was continued for 64 h (71 h total).
Ater cooling to room temperature, the solvent was removed under vacuum (ca. 0.2 Torr) at 25-30C. The oily residue 20 was dried at high ~acuum for 2 h at room temperature, followed by chromatography on 200 g o silica gel (230-400 mesh) using solvent mixtures ranging from ethyl acetate/
petroleum ether 1:1 parts by volume to pure ethyl acetate for elution.
351.2 mg of partially hydrolyzed material containing large amounts of impurities and 571.5 mg (1.82 mmole, 62%) of C3$-[3a,3aa,4a(1E,3*R),5~,5aa]~-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl--1-octenyl)-2H-cyclo-30 penta[b]furan-2-one (oil) were obtained~ Resubjecting the 351.2 mg of partially hydrolyzed material to similar reaction conditions (HOAc, H2O) for 42 h resulted in the formation of 39.6 mg (0.126 mmole) 4.3% o~ additional [3S-~3a,3aa,4a(1E,3*R~,6~,6aa]]-hexahydro-3-~luoro-5-35 hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta-[b]furan-2-one. Total yield of [3S-[3a,3aa,4a(1E,3*R),5~,-6aa]]-hexahydro-3-~luoro-5-hydroxy~4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one was -~Z~ 3~
~ 23 -611.1 m~ (1.94 mmol) 66%, oil, clear.

Example 5 [3S-[3a,3aa,4a(1E,3*R),5~,6aa]3-Hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one 571.5 mg (1.83 mmol) of [3S-C3a,3aa,4a(lE,3*R),5~,-6aa]~-hexahydro-3 fluoro-5-hydroxy-4-(3 hydroxy-4-4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2~one was dissolved ln 20 ml of methylene chlorlde (freshly filtered through aluminum oxide, activity I) under a positive argon pressure.
2.0 ml (21.9 mmol) of dihydropyran (freshly dist. rom sodium) was added under stirring followed by a crystal of p-toluenesulfonic acid monohydrate (9.7 mg; 0.05 mmol).
The mixture was stirred at room temperature for 30 min, poured into 50 ml of sat. aqueous sodium bicarbonate and 20 extracted three times with 30 ml of methylene chloride.
The extracts were washed twice with 50 ml of brine, com-bined, dried over MgS04 and concentrated at reduced pressure. The crude product tl.14 g, oil) was chromato-~raphed on a 100 g silica gel column with ether/petroleum 25 ether (1:1) yielding 797 mg (1.65 mmol) 91% of [3S-[3a,-3aa, 4a( lE,3*R),5~,6aa]]-hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran~2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one as a clear oil (mixture of THP-diastereomers). [a3D -32.46 30 in CHC13, c - 0.8780.

Example 6 [3S-[ 3a, 3aa,4a(1E,3*R),5~,6aa]3-Hexahydro-3 fluoro-5-35 ~(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-ol :~2~

After dissolving 729.2 mg (1.51 mmol) of [3S-[3a,3aa,-4a(lE,3*R),5~,6aa]]-hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-~(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one in 10 ml of toluene (dist. from CaH2) under argon, the mixture was cooled to approx. -70C with a dry ice/acetone bath.
1.25 ml (1.75 mmol) of a 1.4M solu-tion of diisobutylalu-minum hydride in hexane was added dropwise at -70C. The mixture was stirred at -70C for 20 min. 3 ml of a saturated aqueous ammonium chloride solution was added dropwise at -70C and the resulting mixture was transferred with 20 ml of water and 50 ml o~ ethyl acetate into a separatory funnel. Shaking caused a very thick suspension to form, which was filtered through celi~e. The residue was washed thoroughly with 100 ml of ethyl acetate. The ~iltrate was again transferred into a separatory funnel and washed once with 60 ml of brine/water (1:1 parts by volume) and once with 100 ml brine. The a~ueous washings were reextracted once with 30 ml of ethyl acetate. The organic extracts 2~ were combined, dried over MgSO4 and concentrated at reduced pressure. Flash chromatography on 200 y of silica gel (230-400 mesh) of the crude product (806 mg; oil) with ethyl acetate/petroleum ether (4:6) gave 661.5 mg ~1.36 mmol) 90% of [3S-[3a,3aa, 4a(1E,3*R),5~,6aa]]-hexahydro-3-25 fluoro-5-[~tetrahydro-2H-pyran-2-yl)oxy]-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta-[b]furan-2~ol as an amorphous solid, m.p. 58-66C; [a]~5 =
-12.83 in CHC13, c = 1.0290.

(5Z,7R,9a,11a,13E,15R)-7-Fluoro-11,15-di~(tetrahydro-2H-pyran-2-yl)oxy]-16,16-dimethyl-9 hydroxy-prosta-5,13-dien-l-oic acid methyl ester 1.54 g (3.47 mmol) of (4-carboxybutyl)triphenylphos-phonium bromide (dried at high vacuum at 100 over P2O5 for 2 h) and 1.275 g (6.95 mmol) of sodium hexamethyldisilazane

6;3~

(dlst.) were placed into a three neck flask under argon.
20 ml of tetrahydrofuran (freshly dist. from LAH) and 1.25 ml (7.18 mmol) of hexamethylphosphoramide (dist.) were added. This mixture was stirred at room temperature for 1 1/2 h. To the orange red suspension was added drop-wise a solution of 560.5 mg (1.16 mmol) of [3S-[3~,3aa,-4a(lE,3*R),5~,6aa]~hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-ol in 4 ml of tetrahydrofuran. The resulting yellow orange mixture was stirred at room temperature for 4 h. The reaction was quenched by the dropwise addition of glacial acedic acid (faint yellow color). Most of the solvent was evaporated under high vacuum at or below room temperature. The residue 15 was transferred with 100 ml of ether and 100 ml of water into a separatory funnel. The aqueous phase was acidified to pH 3 with 13 ml of lN HCl. ~fter shaking and separation of the two phases, the aqueous phase was reextracted twice with 70 ml of ether. The organic extracts were washed twice 20 with 70 ml of brine, combined and dried over MgSO4. After removal of the solvent, the oily residue was dried at high vacuum for 1 1/2 h, leaving 1.45 g of an oil. This crude acid was dissolved in 10 ml of methylene chloride (freshly filtered through aluminum oxide, activity I) and exterified 2~ at room temperature by the addition of 15 ml (3.75 mmol) of a =.25N solution of diaæomethane in ether. After removal of the solvent at aspirator pressure, the remaining oil (1.27 g~ was dissolved in 10 ml of tetrahydrofuran and 2.8 ml (2.8 mmol) of a l.OM solution of tetra-n-butylammonium 3~ fluoride in tetrahydrofuran was added. The mixture was stirred at room temperature for 15 min, poured into 100 ml of a half concentrated aqueous ammonium chloride solution and extracted three times with 100 ml of ether. The extracts were washed twice with 70 ml of brine, combined, 35 dried over MgSO4 and concentrated at reduced pressure.
1.24 g of a yellow oil was obtained. Chromatography on 100 ~ of silica gel with eth~l acetate/petroleum ether (3:7) (700 ml) followed by ethyl acetate/petroleum ether 6;3~

(1:1 parts by volume) gave 20.8 mg (3.7%) of [3S-[3a,3aa,-4a(lE,3*R),5~,6aa]]-hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-ol (starting material) and 496.3 mg (0.85 mmol) 73% of (5Z,7R,9a,11a,-13E,15R)-7-~luoro-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-16,16-dimethyl-9-hydroxy-prosta-5,13-dien-1-oic acid methylester (oil), as a mixture of diastereomers; [a]D =
+2.74 in CHCl3, c = 0.9116.
Example 8 (7~,9a,11a,13E,15R)-16,16-Dimethyl-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-7-fluoro-5 iodo-prosta-13-en-16 1-oic acid methyl ester 246.9 mg (0.424 mmol) of (5Z,7R,9a,11a,13E,15R)-7-fluoro-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-16,16-dimethyl-9-hydroxy-prosta-5,13-dien-1-oic acid methyl ester 20 was dissolved in 10 ml of acetonitrile (dried over 3A
molecular sieves) under a positlve argon pressur0. 476.9 mg (2.12 mmol, 5 eq.) of N-iodo succinimide was added under stirring, the flask was flushed with argon, closed with a stopper and wrapped in aluminum foil to protect the reac-26 tion mixture from light. The mixture was stirred at roomtemperature for 27 h, poured into 100 ml of a 10% weight by volume solution of sodium thiosulfate in water and extracted three times with 100 ml of methylene chloride.
The organic extracts were washed twi~e with 100 ml of 30 brine, combined, dried over MgSO4 and concentrated at aspirator pressure. 285.9 mg of an oily residue was obtained. Chromatography on 75 g of silica gel with ether/
petroleum ether (1:1 parts by volume) gave 186.8 mg (0.263 mmol) 62% of (7~,9a,11a,13E,15R)-16,16-dimethyl-11,15-35 di[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-7-fluoro-5~iodo-prosta-13-en-1-oic acid methyl ester (oil) as a mixture of diastereomers.

3~

Exam~le 9 (7~,9~,11a,13E,lSR)-16,16-Dimethyl-11,15-dihydroxy-6,9-epoxy-7 fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester 10.6 mg (15 ~mol) of (7~,9~,11~,13E,15R)-16,16-dimethyl-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-7~
fluoro-5-iodo-prosta-13-en-l~oic acid methyl ester was dissolved in a mixture of 3 ml of tetrahydrofuran (freshly 10 dist. from LAH), 6 ml of glacial acetic acid and 3 ml of water under a positive argon pressure. The mixture was heated in an oil bath at 40C and stirred for 19 h. After cooling to room temperature, the solvent was removed at high vacuum at 25. 2 ml of toluene was added and the 15 solvent was again removed at high vacuum at 25. The oily residue (11.2 mg) was chromatographed on a thin layer silica gel plate with ether giving 6.3 mg (11.65 mol, 78%) of (7~,9a,11a,13E,15R)-16,16-dimethyl-ll,lS-dihydroxy-6,9-epoxy-7-fluoro~5-iodo-prosta 13-en-1-oic acid methyl 20 ester (oil) as a mixture of isomers.

Example 10 (52,7~,9a,11a,13E,15~)-7-fluoro 6,9-epoxy-11,15-dihydroxy-25 16,16-dimethyl-prosta-5,13-dien~1-oic acid methyl ester 6.3 mg (11.66 ~mol) of (7~,9~,11~13E,15R)-16,16-dimethyl-11,15-dihydroxy~6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester (mixture of isomers) was 30 dissolved in 2.0 ml of toluene (dist. from CaH2) under a positive argon pressure. 20 ~l (134 ~mol) of 1,8-diaza-bic~clo[5.4.0]undec-7-ene (dist. from CaH2) was added.
With stirring, the mixture was slowly heated to 90C (over 90 min) and kept at 90C for 22 h. After cooling to room 3S temperature, the mixture was poured into 75 ml of half saturated brine and extracted three times with 20 ml of ether. The extracts were washed once with 20 ml of brine, combined, dried over MgSO4 and concentrated at aspirator ~z~

pressure. The remaining oil was drled at high vacuum for 3 h and the 6~2 mg of residual oil was chromatographed on a thin layer silica gel plate with ethyl acetate. Two products were isolated: 3.0 mg (7.27 ~mol) 62% of (5Z,7~,-9~,11a,13E, 15R ) -7-f1UOrO-6,9-ePOXY-11,15-dihYdrOXY-16,16-dimethyl-prosta-5,13-dien-1-oic acid methyl ester (oil) and 1.1 mg (2.66 ~mol) 23% of (4E,6a,7~,9a,11a,13E,lSR)-7-fluoro-6,9-epoxy-ll,lS-dihydroxy-16,16-dimethyl-prosta-4,13-dien-1-oic acid rnethyl ester (oll).
~0 Example 11 (SZ,7~,9a,11a,13E,15R)-7-Fluoro-6,9-epoxy-ll,lS-dihydroxy-16,16~dimethyl-prosta-5,13-dien-1-oic acid sodium salt 3.0 mg (7.27 ~mole) of (SZ,7~,9a,11a,13E,lSR)-7-fluoro-6,9-epoxy-ll,lS-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oic acid methyl ester was dissolved in O.S ml methanol and O.S ml water under argon. 73 ~1 (7.3 ~mole =
20 1 eq.) O.lN sodium hydroxide was added and the mixture was stirred at room temperature for 2 hr~ The methanol was removed at reduced pressure and the remaining aqueous solution was lyophilized to give (5Z,7~,9a,11~,13E,15R)-

7-fluoro-6,9~epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-25 S,13-dien-1-oic acid sodium salt as a white powder; m.p.
48-51C.

Exam 30 [3aR-[3aa~4a(lE~3R*~4R*)6aa]]-Hexahydro-4-[[[3-(l~l-dimeth ethyl)dimethylsilyl]oxy]-4 fluoro-1-octenyl]-2H-cyclopenta-~b~furan-2-one By the procedure of Example 1 [3aR-[3aa,4a(1E,3R*,-35 4R*)6a~]]-hexahydro-4-[4-fluoro-3-hydroxy-1-octenyl)-2H-cyclopenta[b]furan-2-one was converted to [3aR-[3aa,4a-(lE,3R*,4R*)6aa]]-hexahydro-4-[[[3-(1,1-dimethylethyl)-dimethylsilyl]oxy]-4-fluoro-1-octenyl)-2H-cyclopenta[b]-~86~

furan-2-one.

Example 13 C3aR-c3aa~4a(lE~3R*~4R*)6aa]]-Hexahydro-3-fluoro-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one By the procedure of Examples 2 and 3, C3aR-[3aa,4a-10 (lE,3R*,4R*)6aa]~-hexahydro-4-[[[3-11,1-dimethylethyl)-dimethylsilyl]oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]-furan-2-one was converted to [3aR-[3aa,4a(lE,3R*,4R*)6aa]]-hexahydro-3-fluoro-4-C[C3-(1,1-dimethylethyl)dlmethyl-silyl]oxy]-4-fluoro-1-octenyl]~2H-furan-2-one.
1~;
Example 1 4 [3aR [3aa,4~(1E,3R*,4R*)6aa]]-Hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopentaCb]furan-2-one By the procedure of Example 4 [3aR-[3aa,4a(1E,3R*,-4R*)6aa]]-hexahydro-3-fluoro-4-[[C3~ -dimethylethyl)-dimethylsilyl]oxy]-4-fluoro-1-octenyl]-2H-cyclopentaCb]-furan-2-one was converted to C3aR-C3aa,4a(1E,3R*,4R*)6aa]]-25 hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopentaCb]furan-2-one.

Example 15 30 C3aR-[3aa,4allE,3R*,4R*)6aa]]-Hexahydro 3-fluoro-4-C3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-o~tenyl]-2H-cyclopenta[b]furan-2-one By the procedure of Example 5 [3aR-[3aa,4a(lE,3R*,-35 4R*)6aa]]-hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopentaCb]furan-2-one was converted to ~3aR-C3aa,4a(1E,3R*,4R*)6aa]]-hexahydro-3-fluoro--4-c3-C(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-l-octenyl]-2H-3~
_ 30 -cyclopenta[b]furan-2-one.

Example 16 [3aR-[3a~,4a(1E,3R*,4R*)6aa]]-Hexahydro~3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-~-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-ol ~y the procedure of Example 6 [3aR-[3aa,4a(1E,3R*,-10 4R*)6aa]]-hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one was converted to [3aR-[3aa,4a(lE,3R*,4R*)6aa]]-hexahydro-3-fluoro-4-[3-[(tetrahydro-pyran-2-yl)oxy]-4-fluoro~1-octenyl]-2H-cyclopenta[b]furan-2-ol.

(5Z,9a,13E,15R,16R)-7,16-Difluoro 15-[(tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-5,13-dien-1-oic acid methyl ester By the procedure of E:xa~le 7 [3aR-[3aa,4a(1E,3R*,-4R*)6aa]]~hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-ol was converted to (5z~9a~l3E~l5R~l6R)-7~l6-difluoro-l5-25 [(tetrahydro-2H-pyran-2-yl)oxy~-9-hydroxy-prosta-5,13-dien-1-oic acid methyl ester.

Example 18 30 (9a~l3E~l5R~l6R)-7~l6-Difluoro-l5-[(tetrahydro-2H-pyran-2 yl)oxy]-6,9-epoxy-5-iodo-prosta-13-en-1-oic acid methyl ester By the procedure of Example 8, (5Z,9,13E,15R,16R)-35 7,16-difluoro-15-[(tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-prosta-5,13-dien-1-oic acid methyl ester was converted to (9a,13E,15R,16R)-7,16-difluoro-15-[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-5-iodo-prosta-13-en-1-oic acid methyl ester.

Example 19 (9~,13E,15R,16R)-7,16-Difluoro-lS-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-oic acid methyl ester By the procedure of Example 9, (9a,13E,lSR,16R)-7,16-difluoro-lS-[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-S-10 iodo prosta-13-en-1-oic acid methyl ester was converted to (9~,13E,15R,16R)-7,16-difluoro-lS-hydroxy-6,9-epoxy-S-iodo-prosta-13-en-1-oic acid methyl ester.

Example 20 (SZ,9a,13E,15R,16R)-7,16~Difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oic acid methyl ester By the procedure of Example 10 (9a,13E,15R,16R)-7,16-20 difluoro 15-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-oic acid methyl ester was converted to (5Z,9a,13E,15R,16R)-7,16-difluoro-15-hydroxy-6,9-epoxy~prosta-5,13-dien-1-oic acid methyl ester.

Example 21 (5Z,9a,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oic acid sodium salt By the procedure of Example 11, (5Z,9a,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oic acid methyl ester was converted to (5Z,9a,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13~dien-1-oic acid sodium salt.
3~

- 32 ~

Example 22 (4E,9a,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oic acid methyl ester By the procedure of Example 10, (9a,13E,15R,16R)-7,16-difluoro-lS-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-oic acid methyl ester was converted to (4E,9a,13E,lSR,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oic 10 acid methyl ester.

Example _3 ~y the procedure of Example 11, (4E,9a,13E,15R,16R)-15 7,16-difluoro-6,9-epoxy-15-hydroxy prosta-4,13-dien-1-oic acid methyl ester was converted to the sodium salt of (4E,9a,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oic acid.

Example 24 A tablet was found containing:

Per Tablet 25 (5z~9a~l3Ell5R~l6R)-7~l6-Difluoro 6,9-epoxy-15-hydroxy-prosta~5,13-dien-1-oic acid sodium salt 25 mg Dicalcium phosphate dihydrate, unmilled 175 mg Corn Starch 24 mg 30 Magnesium stearate 1 mq Total Weight 225 mg .

The active ingredient and corn starch were mixed together and passed through a ~00 screen in Model "J"
35 Fitzmill with hammers forward. This premix was then mixed with dicalcium phosphate and one-half of the magnesium steaxate, passed through a ~lZ screen in Model "J" Fitzmill with kniver forward, and slugged. The slugs were passed

8~34~
_ 33 -through a ~2A plate in a Model "D" Fitzmill at slow speed with knives forward and the remaining magnesium stearate was added. The mixture was mixed and compressed.

Example 25 A tablet was formulated in the same manner as in Example 24 except that (4E,9a,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oic acid methyl ester was the active ingredient.

Example 26 A capsule was prepared containing the ~ollowing 15 ingredients:

Per Tablet (5Z,9a,13E,lSR,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oic acid sodium salt 200 mg Dicalcium phosphate dihydrate, unmilled 235 mg Corn Starch 70 mg FD & C Yellow ~5 - Aluminum Lake 25% 2 mg Durkee Duratex* 25 mg 25 Calcium Stearate 3 mq 535 mg * Hydrogenated cotton seed oil (fully saturated) All of the above ingredients were mixed until thoroughly blended in a suitable size container. The powder was filled in to ~2, two-piece, hard-shell gelatin capsules to an approximately fill weight of 350 mg using a capsulating machineO

- 3~ -Example 27 A capsule was prepared by the procedure of example 24 except that (4E,9a,13E, 15R ,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oic acid mathyl ester was the actlve ingredient.

Example 28 10 3,3aS,4,5,6,6aS Hexahydro-3--fluoro-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-one To a solution of diisopropylamine in 9 ml of THF
15 (tetrahydrofuran) cooled to 0-5C, was added dropwise 1.32 ml of a 2.2M solution of n-butyl lithium in hexane.
The mixture was stirred for 5 min and cooled to -40C with a dry ice acetone bath. A solution of 1 g of 3,3aR,4,5,6,-6aS-hexahydro-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-20 1-trans-octenyl]~5R-methyl-2H-cyclopenta~b]furan-2-one in 6 ml of THF (tetrahydrofuran) was added ropwise over 1 minute and stirred at -45C for 5 min. Trimethylchlorosilane (4.26 ml) was then added and ~he mi~ture stirred a~ -40C
for 5 min. The mixture was then allowed to warm to 0C
25 and the solvent removed under high vacuum. Dlethyl ether (5 ml) was added to the residue and the cold mixture filtered through a sintered glass funnel. The solvent was then removed under high vacuum ~ice bath) and the residue dissolved in 10 ml of CH2Cl2. To the solution at 0C was 30 then added 530 mg of potassium bicarbonate followed by 429 mg of xenon difluoride. After the gas evolution ceased, the mixture was stirred for an additional 15 min and diluted with 50 ml of CH2Cl2. The solution was then washed with 50 ml of H2O + 2 x 50 ml of brine. The aqueous phase 35 was separated and back washed with 50 ml of CH2Cl2. The organic layers were combined, driad (MgSO4) and the solvents removed under reduced pressure to give 0.95 g of crude product. chromatography on 50 g of silica gel afforded 6~
_ 35 -300 mg of 3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)~ rans-octenyl]-5R-methyl-2H-cyclopenta[b]furan.

Example 29 3,3aS,4,5,6,6aS-Hexahydro-3-fluo~o-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-trans-octenyl]-SR-methyl-2H-cyclopenta~b]furan-2-ol By the procedure of Example 6, 3,3aS,4,5,6,6aS-hexa-hydro-3-fluoro-4R-[4,4-dimethyl-3~-(2-tetrahydropyranyloxy) 1-trans octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-one was converte~ to 3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-16 [4,4-dimethyl-3R (2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-ol.

Example_30 20 1 1R ,16,16-Trimethyl-7-fluoro-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoic acid ~ethyl ester By the procedure of Example 7, 3,3aS,4,5,6,6aS-hexa-hydro-3-fluoro-4R-[4,4-dimethyl-3R-(2-~etrahydropyranyloxy)-2~ l-trans-octenyl]-sR-methyl-2H-cyclopentacb]furan-2-ol was converted to 11R ,16,16-trimethyl-7-fluoro-15R-(2-tet~ra-hydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoic acid methyl ester.

Example 31 (9S,llR,13E,15R ) -11,16,16-TXimethY1-15-(2-tetrahYdrO-pyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester 3~ .
By the procedure of Example 8, llR,16,16~trimethyl-7-fluoro-lSR-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5~trans-13-dienoic acid methyl ester was con~erted to ,~ .

i3~

(9S,llR,13E,15R)-11,16,16-trimethyl-15-(2-tetrahydro-pyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester.

Example 32 (9S~llR~13E~15R)-11,16~16-Trimethyl-15-hydroxy-6~9-epoxy-7-fluoro-5-iodo-prosta-13 en-1-oic acid methyl ester By the procedure of Example 9, (9S,llR,13E,15R)-11,16,16-trimethyl~15-(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester was converted to (9S,llR,13E,15R)-11,16,16 trimsthyl-15-hydroxy-6, 9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid 15 methyl ester.

Example 33 (5Z,9S,llR,13E,15R)-11,16,16-Trimethyl~15-hydxoxy-6,9-20 epoxy-7~fluoro-prosta-5,13-dien-1-oic acid methyl ester and (4E,9S,llR,15R)-11,16,16 trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-4,13-dien-1-oic acid methyl ester By the procedure of Example 10, (9S,11R,13E,15R)-26 1l~l6~l6-trlmethyl-l5-hydroxy-6~9-epoxy-7-fluoro-5-iod prosta-13-en-1-oic acid methyl ester was converted to a mixture which was separated by the procedure of Example 10 to (SZ,9S,llR,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oic acid methyl ester.
Calc. for C24H39FO4 C 70.21, H 9.57, F 4063 Found C 70.00, H 9.44, F 4.49 ir 3615, 1733, 1694 cm 1; ultraviolet A max 213 nm ( =
12000) 35 and (4E,9S,llR,15R)-11,16,15-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-4,13~dien-1-oic acid methyl ester, ,~

;3~

Calc. C 70.21, H 9~57, F 4.63 Found C 70.19, H 9.52, F 4.85 ir 3615, 1735, 1670 cm 1.

Example 34 (5Z,9S,llR,13E,15R)-11,16,16-Trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13~dien-1-oic acid sodium salt By the procedure of Example 11, (5Z,9S,llR,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oic acid methyl ester was converted to (5Z,9S,-llR,13E,15R)~11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1 oic acid sodium salt.

3,3aS,4,5,6,6aS-Hexah~dro-3-fluoro 4R-[3S-(2-tetrahydro-pyranyloxy)-l-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-20 2H-cyclopenta[b]uran-2 one By the procedure of Example 28, 3,3aR,4,5,6,6aS-hexa-hydro-4R-C3S-(2-tetrahydropyranyloxy)-l-trans-octenyl]-5R-(2-~etrahydropyranyloxy)-2H-cyclopenta[b]furan-2-one was 2~ converted to 3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetra-hydropyranyloxy)-2H-cyclopenta[b]furan-2-one.

Exam~le 36 , 3,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[3S-(2-tetrahydro-pyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-one 3~ By the procedure of Example 6, 3,3aS,4,5,6,6aS-hexa-hydro-3-fluoro-4R-[3S-(2-te~rahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-one was converted to 3,3aS,4,5,6,6aS-hexahydro-3-fluoro-3~

4R-[3S-(2-tetrahydropyranyloxy)-1-trans octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]~uran-2-ol.

Exam~e 37 llR,15S-Di-(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-dienoic acid methyl ester By the procedure of Example 7, 3,3aS,4,5,6,6aS-hexa-10 hydro-3-fluoro-4R~[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-ol was converted to llR,15S-di-(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-dienoic acid methyl ester.

Example 38 (9S,llR,13E,15S)-11,15-Di-(2-tetrahydropyranyloxy) 6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester By the procedure of Example 8, llR,15R-di-(2-tetra-hydropyranyloxy)-7-~luoro-9S-hydroxy-prosta-cis-5-trans-13-dienoic acid methyl ester was converted to (9S,llR,-13E,15S)-11,15-di-(2-tetrahydropyranyloxy)-6,9-epoxy-7-25 fluoro-5 iodo-prosta-13-en-1-oic acid methyl ester.

Example 39 ( 9S, 11R ,13E,15S)-11,15-Dihydroxy-6,9-epoxy-7-fluoro-5-30 iodo-prosta-13-en-1-oic acid methyl ester By the procedure of Example 9, (9S,llR,13E,15S)-11,15-di-(2-tetrahydropyranyloxy) 6,9 epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester was converted 3~ to (9S, 11R ,13E,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid methyl ester.

` ~2~6~34 Example 40 (5Z,9S, 11R ,13E,15S)-11,15-Dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oic acid methyl ester and (4E,9S,11R ,-15R)-11,15-dihydroxy-6,9-epoxy-7-fluoro-4,13-dien-1-oic acid methyl ester By the procedure of Example 10 (9S,llR,13E,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-10 oic acid methyl ester was converted to a mixture which was separated in accordance with the procedure o Example 10 to produce (5Z,9S, 11R ,13~,15S)-11,15-dihydroxy-6,9-epoxy-7~fluoro-prosta-5,13-dien-1-oic acid methyl ester and (4E,9S,llR,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-15 4,13-dien-1-oic acid methyl ester.

Example 41 (5Z,9S,llR,13E,15S)-11,15-Dihydroxy-6,9-epoxy-7-fluoro-20 prosta-5,13-dien-1-oic acid sodium salt By the procedure of Example 11, (5Zj9S,llR,13E,lSS)-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-die~-1-olc acid methyl ester was converted to (5Z,9S,llR,13E,15S~-11,15-25 dihydroxy-6~9-epoxy-7-luoro-prosta-5~l3~dien-l oic acid sodium salt.

Claims (14)

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

1. A process for the preparation of compounds of the formula I

wherein one of the double bonds indicated by broken lines is present in 4,5 or 5,6 position, R is hydrogen or lower alkyl, R1 is methyl, hydrogen or hydroxy;
R2 is hydrogen, methyl or fluoro; and R21 is hydrogen, fluoro, trifluoromethyl or methyl; with the proviso that when R21 is trifluoromethyl, R2 is hydrogen or methyl, their pharmaceutically acceptable salts, optical anti-podes or racemates which comprises dehydrohalogenating, a compound of the formula . XII

wherein X is halogen; R6 is lower alkyl; and R1, R2 and R are as above, and, if desired, hydrolyzing the ester group R and, if further desired, converting the carboxylic acid so obtained into a pharmaceutically acceptable salt.

2. A process as in claim 1 wherein a compound of the formula IA

wherein R, R1, R2 and R21 are as in claim 1, is prepared.

3. A process as in claim 1 wherein a compound of formula I is prepared wherein the 7-fluoro substituent is in the beta configuration.

4. A process as in claim 1 wherein a compound of formula I is prepared wherein R1 is hydroxy or methyl and R2 and R21 are methyl or R2 is hydrogen and R21 is fiuoro.

5. A process as in claim 1 wherein (5Z,7.beta.,9.alpha.,11.alpha.,-13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16--dimethyl-prosta-5,13-dien-1-oic acid sodium salt is prepared.

6. A process as in claim 1 wherein (5Z,7.beta.,9.alpha.,11.alpha.,-13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16--dimethyl-prosta-5,13-dien-1-oic acid methyl ester is prepared.

7. A process as in claim 1 wherein (5Z,9S,llR,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oic acid methyl ester is prepared.

8. A compound of the formula I given in claim 1, whenever prepared according to the process of claim 1 or by an obvious chemical equivalent thereof.

9. A compound of claim 8 having the formula wherein R, R1, R2 and R21 are as in claim 1, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

10. A compound as in claim 8 wherein the 7-fluoro substituent is in the beta configuration, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

11. A compound as in claim 8 wherein R1 is hydroxy or methyl and R2 and R21 are methyl or R2 is hydrogen and R21 is fluoro, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

12. (5Z,7.beta.,9.alpha.,11.alpha.,13E,lSR)-7-Fluoro-6,9-epoxy-11,15-dlhydroxy-16,16-dimethyl-prosta-5,13-dien-1-oic acid sodium salt, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

13. (5Z,7.beta.,9.alpha.,11.alpha.,13E,15R)-7-Fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oic acid methyl ester, whenever prepared by the process of cla1m 6 or by an obvious chemical equivalent thereof.

14- (5Z,9S,llR,13E,15R)-11,16,16-Trimethyl-15-hydroxy-6,9-epoxy-7-fluoro prosta-5,13-dien-1-oic acid methyl ester, whenever prepared by the process of alaim 7 or by an obvious chemical equivalent thereof.