CH651033A5 - Fluorprostacycline. - Google Patents

Description

651033

2nd

Compounds of formula h

'<X

PATENT CLAIM

o a

h-ch2-ch2-ch2-c-0r for r3

r1

"^ ch = ch-cpi -c -ch2-ch2-ch2-ch3

'4' 2

or r wherein R is lower alkyl; R1 is hydrogen, methyl or -OR4, R2 or an ether-hydrolyzable ether protecting group methyl, hydrogen or fluorine; R3 represents fluorine, hydrogen, tri-; where R2 is hydrogen or methyl when R3 is trifluoromethyl or methyl; X halogen; and -OR4 hydroxy 20 is fluoromethyl.

The present invention relates to new fluorostacy clines of the general formula

0

cho-ch „-c-0r

£ ä Ù L

R3

"^ ch = ch-ch -c -ch0-ch0-ch0-chq li ù ù ù o

I ". I.

4?

or r

wherein R is lower alkyl; R1 is hydrogen, methyl or -OR4, R2 is methyl, hydrogen or fluorine; R3 fluorine, hydrogen, trifluoromethyl or methyl; X halogen; and -OR4 represents hydroxy or an acid hydrolyzable ether protecting group; where R2 is hydrogen or methyl when R3 is trifluoromethyl.

The term "lower alkyl" used here refers to straight-chain and branched alkyl groups with 1-7 C atoms such as methyl and ethyl. Unless otherwise stated, the term "halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

According to the invention, all compounds with one or more asymmetric carbon atoms can be produced in the form of racemates. These racemates can be cleaved at a suitable point in the production process in a manner known per se, whereupon the subsequent products can be obtained as optically pure enantiomers. On the other hand, optically active enantiomers or racemates of the formula I can be obtained depending on the optical form of the compound of the formula II used as the starting material.

In the structural formulas given here, a wedge-shaped line means a substituent in the β position (above the molecular level), a broken line means a substituent in the a position (below the molecular level) and a wavy line means a substituent which is either a or β position has, or mixture of these isomers. Of the

Structural formulas are only shown in one form, but should be understood to include other forms including the enantiomers and racemates.

The term “an ether-45 protective group that can be hydrolyzed by acid” denotes any ether which gives a hydroxyl group by acid-catalyzed cleavage. A suitable ether protecting group is, for example, tetrahydropyranyl ether or 4-methyl-5,6-dihydro-2H-pyranyl ether.

Other protective groups are aryl methyl ethers such as benzyl, 5 'benzhydryl or trityl ether; or a-lower alkoxy lower alkyl ether, for example methoxymethyl; or allylic ether or tri (lower alkyl) silyl ether such as trimethylsilyl ether or di-methyl-tert-butylsilyl ether. Preferred are t-butyl, tetrahydropyranyl and tri (lower alkyl) silyl ether, especially dimethyl t-butyl ether. The acid catalyzed cleavage is carried out by treatment with a strong organic or inorganic acid. Preferred inorganic acids are mineral acids such as sulfuric acid and hydrohalic acids. Preferred organic acids are lower alkane carboxylic acids such as acetic acid,

and p-toluenesulfonic acid. The acid-catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent. If an organic acid is used, it can serve as a solvent. 65 In the case of a t-butyl group, the acid that forms the solvent is generally used. In the case of tetrahy dropyranyl ethers, the cleavage is generally carried out in an aqueous medium. Thereby are temperature and

3rd

651033

Pressure is not critical and the reaction can be carried out at room temperature and atmospheric pressure.

The compounds of the formula I can be obtained from compounds of the formula

O

r-

^ ch = ch-ch-c-ch.-ch9-ch9-ch,

II

r1

Ii oh r in which R2 and R3 have the above meaning, and R111 represents hydrogen, methyl or hydroxy, via which compounds IV to XI are prepared:

O

ä * 1

ch = ch-ch -c -ch2-ch -ch -ch3

IY

- 411 ■ or r '

r'3-

ck = crî-ch -c -ch2-ch2-ch9-ch

V

or41r2

r-

VI

iP

^ ch = ch-ch -c _ch2 ~ ch2 ~ ch2 ~ ch3

or'3

j ^ Ir 2

651033

O

■ ^ Lli r

ch = ch-çh-c -c ^ -ch2-ch2-ch3 fH r2

VII

oh r

m ch = ch-ch -c -ch - ch -ch - cii,

il z /. a or

% [2nd

VIII

ho

\\ U

J?

ch = ch-ch2-ch2-ch -cooh »

^ ch = ch-ch -c ch -ch -ch -ch-

—I I T L L L i r

or

'2

41R

ho.

, ^ ch -ch = ch-ch2 ~ ch2-ch2-coor

R-I

ch = ch-çi-i -ç — ch -ch, -ch -ch

1I A-4! 2 ù ** L 0

R OR R

X

In the above formulas, R, R2 and R3 have the above a tri (lower alkyl) chlorosilane as an etherifying agent in

Importance; R11 is hydrogen, methyl or OR41; R111 is the presence of an organic base such as imidazole or

Hydrogen, methyl or hydroxy; OR41 is an acid ss pyridine. Conventional hydrolyzable ether protecting groups; R is lower alkyl; and organic amine bases are used.

R5 is tri (lower alkyl) silyl. A compound of formula IV is converted into a compound

A compound of formula II can be converted to conventional one of formula V by first

Etherification converted into a compound of formula IV enolized formula IV and then with a trialkyl

are treated to free hydroxy groups in the compound of 60 halosilane. The enolization can in itself

Protect Formula II. If R111 done in the connection in the known manner. They are preferably treated

Formula II is hydroxy, the hydroxy group is replaced by this compound of formula IV with a non-aqueous alkali

Etherification in an ether group of the compound IV metal base. Preferred bases for this purpose are changing. Preferred ethers for this purpose are tetrahy lithium diisopropylamide or sodium hexamethyldisilazane.

dropyranyl and dimethyl-6-butylsilyl ether. When Reacting This Reaction Using the ion can be any conventional method of etherifying the non-aqueous alkali metal bases in general

Compound of formula II can be used. If a temperature of -70 to -30 ° is preferred. The reaction is tri (lower alkyl) silyl ether is desired, is generally used in an inert organic solvent

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carried out. Any conventional inert organic solvent that is liquid in the aforementioned temperature range can be used. The preferred solvent is tetrahydrofuran. The enolate of the compound of formula IV can be converted as an alkali metal salt into a compound of formula V by treatment with a trialkylhalosilane, preferably trimethylchlorosilane. This reaction is usually carried out at the same temperatures and with the same solvent used in the formation of the enolate.

The compound of formula V is converted to a compound of formula VI by treatment with a fluorinating agent. Any conventional fluorinating agent can be used for this. Xenon di-

fluoride and gaseous fluorine. In general, the reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be used. Halogenated hydrocarbons such as methylene chloride or carbon tetrachloride are preferred. Temperature and pressure are not critical to the reaction, and can be carried out at room temperature and atmospheric pressure. Although room temperature can be used, it is preferred to work at low temperatures, i.e. from -10 to + 10 ° C.

When the compound of the formula V is converted into a compound of the formula VI, the compound of the formula VI is mixed as a mixture of the compounds of the formulas r

11

r3

^ ch = ch-ch -c -ch2-ch2-ch2-ch3

- 441 2 or r

VIA

- \ u f r ~

VI-B

ch = ch-ch -c -ch2-ch2 "ch0-ch3

or41r2

where R ", R2 and R3 have the meaning given above.

The compounds of the formulas VI-A and VI-B can be separated by customary means, such as chromatography. On the other hand, the compound of formula VI can be used as a mixture of the compound of formula VI-A and VI-B for the remaining reaction stages or a separation can be carried out at a later stage in order to obtain a compound of formula I with the desired fluorine orientation in 7- Get position. When the compound of formula VI is separated into the compound of formula VI-A and VI-B, the configuration of the fluorine atom is maintained in the course of the usual reaction sequence. If, therefore, compounds of the formula I with 7β-fluorine are desired, a compound of the formula VI-A is used, the intermediates of the formula VII-VIII, in which the fluorine atom has the β configuration, being obtained. If compounds of the formula I with 7a-fluorine substitution are desired, the starting point is a compound of the formula VI-B, the fluorine atom having the a configuration in the intermediates of the formula VII.

On the other hand, the compounds of the formula VI can be used without separating them into the compound of the formulas VI-A and VI-B. In this way, compounds of formula I in which fluorine is both a- and

has the β configuration, via the intermediates of formula 45 VII-VIII, in which the fluorine atom occupies the same position.

When converting the compounds of formula II into the compound of formula VI, tri (lower alkyl) silyl ether is generally preferably used as the hydroxyl-50 protective group. When converting the compound of formula VI into a compound of formula I, it is generally preferred to protect one or more hydroxy groups as tetrahydropyranyl ether. On the other hand, silyl ether or any other conventional ether group can be used in the 55 remaining process steps. According to the preferred embodiment, silyl ethers of the formula VI are hydrolyzed, giving compounds of the formula VII which are then esterified again and form compounds of the formula VI in which the ether groups are a tetra-6o hydropyranyl group. Any conventional hydrolysis or etherification method 65 can be used for the hydrolysis of compounds of the formula VI to compounds of the formula VII and the subsequent re-etherification of the compound of the formula VII to a compound of the formula VI. If the protecting group in the compound of formula VI is tetrahydropyranyl, there is no need to hydrolyze the compound of formula VI to the compound of formula VII because the compound

651033

of formula VÏII can be obtained directly from the compound of formula VI.

A compound of formula VII is converted to a compound of formula VIII by treatment with a reducing agent. Any conventional reducing agent that selectively reduces a keto group to the hydroxy group is suitable for this. Preferred reducing agents are hydrides, preferably aluminum hydrides such as alkali metal aluminum hydrides and borohydrides such as alkali borohydrides, with diisobutyl aluminum hydride being particularly preferred. The reaction can also be carried out using di (branched-chain-lower-alkyl) boranes such as bis (3-methyl-2-butyl) borane. In this reaction, temperature and pressure are not of critical importance; one can work at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. In general, it is preferable to carry out the reaction at a temperature from -80 ° C to the reflux temperature of the reaction mixture. The reduction can be carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be used. Dimethoxyethylene glycol and ether such as tetrahydrofuran, diethyl ether and dioxane are preferred.

Compounds of formula IX can be obtained from compounds of formula VIII by reaction with a phosphonium salt of the formula

Rb

I.

O

Ra-p-cm-cm-cm-CHzC-OH

I (+)

rc y (-)

XX-A

(CH _) _ COOR 4 ^ £ Z.

III

r

III

R

CH = CH-Ctf-C- (CH2) 3CH3

HO R

, • 3

15

wherein R1, Rb, Rc is aryl or di (lower alkyl) amino and Y is halogen, can be obtained by a conventional Wittig reaction. The reaction conditions known per se for Wittig reactions can be used for this reaction.

The compound of formula IX can be converted to a compound of formula X by esterification with diazomethane or a reactive derivative of a lower alkanol, such as a lower alkyl halide. The usual reaction conditions for esterifications can be used for this.

A compound of formula X can be converted to a compound of formula I by treatment with a halogenating agent. Preferred halogenating agents are N-halosuccinimides, in particular N-iodosuccinimide. In general, this reaction is carried out in the presence of a polar solvent such as acetonitrile or halogenated hydrocarbons such as methylene chloride or ethylene chloride. Any conventional polar organic solvent can be used. The reaction temperatures can be 0-35 ° C. In general, it is preferred to work at room temperature.

In a compound of formula I, an ether protecting group can be hydrolyzed. Any conventional ether hydrolysis method can be used for this. In general, mild acidic hydrolysis, such as aqueous acetic acid, is used.

The compounds of the formula I can be converted into compounds of the formula in which R, RU1, R2, R3 and the dashed double bonds have the meaning given above by treatment with a dehydrohalogenating agent.

The compounds of formula III and their pharmaceutically acceptable salts, as well as the optical antipodes and 20 racemates thereof, are effective as antisecretory agents, antihypertensives, anti-ulcerogenic agents and can be used to combat gastro-hyperacidity and as agents for inhibiting platelet aggregation.

25 Example 1

246.9 mg (5Z, 7R, 9ct, l la, 13E, 15R) -7-fluoro-l l, 15-di [(tetra-hydro-2H-pyran-2-yl) oxy] -16.16- dimethyl-9-hydroxyprosta-5,13-diene-l-acidic acid methyl ester was dissolved in 10 ml of acetonitrile (dried over 3 A molecular sieve) under argon. 30 Then 476.9 mg of N-iodosuccinimide were added with stirring, the reaction vessel was flushed with argon, sealed and protected from light with aluminum foil. The mixture was stirred at room temperature for 27 hours, poured into 100 ml of a 10% by weight aqueous sodium thiosulfate solution and extracted three times with 100 ml of methylene chloride. The organic extracts were washed twice with 100 ml of brine, dried over magnesium sulfate and evaporated. 285.9 mg of an oily residue were obtained, which was chromatographed on 75 g of silica gel with ether / petroleum 40 ether (1: 1 parts by volume) and 186.8 mg (62%) (7β, 9a, 11 a, 13 U, 15R) -16,16-dimethyl-11,15-di [(tetrahydro-2H-pyran-2-yl) oxy] -6,9-epoxy-7-fluoro-5-iodine prosta-13-en-1 -Acid methyl ester (oil) as a mixture of diastereomers.

45

Preparation of the starting material: a) 502.2 mg {3aR- [3aa, 4a (IE, 3R *) 5β, 6aa]} - hexahydro-5-hydroxy-4- (3-hydroxy-4,4-dimethyl-1 - octenyl) -2H-cyclo-penta [b] furan-2-one was dissolved in 15 ml dimethylformamide (reagent quality, dried over 3 A molecular sieve) under argon. 1.045 g of t-butyldimethylchlorosilane (previously distilled) and 587.6 mg of imidazole (reagent quality) were added to the solution. The resulting mixture was stirred at room temperature for 18 hours, poured into 60 ml of ice-cold 0.5N hydrochloric acid and extracted three times with 60 ml of diethyl ether. The extracts were washed with 60 ml of a mixture of saturated aqueous sodium bicarbonate solution, water and brine (1: 1: 2) and then with 60 ml of brine. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. 1.25 g of a white semi-solid was obtained. The crude product was chromatographed on 75 g of silica gel, first with 11 a mixture of 10% by volume ether and 90% by volume petroleum ether and then with a mixture of 20% by volume ether and 80% by volume. % Petroleum ether was eluted. 857.1 mg of {3aR- [3aa, 4a (IE, 3R *) - 5β, 6aa]} - hexahydro-5 - {[(1,1 -dimethylethyl) dimethylsilyl] oxy} -4 - ({[3 - (l, 1 -dimethylethyl) -dimethylsilyl] oxy} -4,4-dime-

651033

thyl-l-octenyl) -2H-cyclopenta [b] furan-2-one as a white amorphous solid with a melting point of 67-68 °.

b) 579 ml of diisopropylamine distilled over calcium hydride were dissolved in 15 ml of tetrahydrofuran freshly distilled over lithium aluminum hydride. The mixture is cooled to + 3 ° under nitrogen and 2.5 ml of a 1.5N solution of n-butyllithium in hexane are added dropwise at this temperature. After stirring for 5 minutes at the same temperature, the mixture was cooled to -40 ° and added dropwise with a solution of 1.757 g {3aR- [3 aa, 4a (1 U, 3 R *) 5β, 6act]} - hexahydro-5 - {[(1,1-dimethylethyl) dimethylsilyl] oxy} -4 - ({[3- (1,1-dimethylethyl) dimethylsilyl] oxy} -4,4-dimethyl-1-octenyl) -2H -cyclopenta [b] furan-2-oa in 6 ml of tetrahydrofuran. After 5 minutes of stirring at -40 °, 570 ml of trimethylchlorosilane were added rapidly. After 2 minutes the cooling bath was removed and the mixture was allowed to warm to + 15 ° over 20 minutes. The solvent was removed under reduced pressure at a temperature not above room temperature 20 and the residue was dried under high vacuum for 15 minutes. Thereafter, 10 ml of ether (freshly filtered over aluminum oxide, activity I) was added under argon and the mixture was filtered off. The white residue was washed three times with 3 ml of ether. The light yellow filtrate was concentrated under reduced pressure and the oily residue was dried in a high vacuum (room temperature) for 1 hour, {3aR- [3aa, 4oc (1 E, 3 R *) 5β, 6aa]} - 4.5, 6,6a-tetrahydro-5 - {[(1,1-dimethylethyl) dimethylsilyl] oxy} -4 - ({[3 - (1,1-dimethylethyl) dimethylsilyl] oxy} -4,4-dimethyl-1-octenyl ) -2- (trimethylsilyl) 30 oxy-3aH-cyclopenta [b] furan.

The compound prepared in b) was dissolved in 15 ml of methylene chloride (fresh over aluminum oxide, activity I) under argon. The mixture was cooled to + 2 ° and 680 mg of potassium bicarbonate (dried under high vacuum for 3 hours over phosphorus pentoxide at 100 °) and 632.9 mg of xenon difluoride were successively added with stirring. In the first 30 seconds after the addition of the xenon difluoride, violent gas evolution started. The mixture was stirred at + 2 ° for 40 minutes, poured into 150 ml of ice water and extracted three times with 150 ml of methylene chloride. The extracts were washed twice with 150 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dried under high vacuum 18 for 45 hours, leaving 1.92 g of a yellowish oil.

d) The crude product was added to 200 g of silica gel (230-50

400 mesh) chromatographed (flash chromatography). 11 of a solvent mixture of 5% by volume of ethyl acetate and 95% by volume of petroleum ether and then petroleum ether with 10% by volume of ethyl acetate were used as eluents. The following products were eluted in succession: 1.06 g (58%) {3S- [3aa, 4a (I E, 3 * R) 5β, 6aa]} - hexa-hydro-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 -on, white needles with melting point 49-51 °; 165.2 mg (9.4%) {3aR- [3aa, 4a- 60

(1E, 3 * R) 5ß, 6aa]} - Hexahydro-5 - {[(1,1 -dimethylethyl) -dimethylsilyl] oxy} -4 - ({[3- (l, 1 -dimethylethyl) dimethylsilyl ] oxy} -4,4-dimethyl-1-octenyl) -2H-cyclopenta [b] furan-1 -one (starting material); and 98.9 mg (5.4%) 3R- [3ß, 3aa, 4a (IE, 3 * R) 5ß, 6aaJ-hexahydro-3-fluoro-5 - {[(l, l-dimethylethyl) dime- 65 thylsilyl] oxy} -4 - ({[3- (1,1-dimethylethyl) - dimethyl silyl] oxy} -4-4-dimethyl-1-octenyl) -2H-cyclopenta [b] furan- 2-one, amorphous white solid with a melting point of 83-85 °.

e) l, 597g {3S- [3aa, 4a (lE, 3 * R) 5ß, 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 was dissolved in 60 ml acetic acid (reagent quality) and under argon heated to 55 °. 6 ml of water were then added with stirring. After 7 hours a further 4 ml of water was added and the mixture was stirred at 55 ° for a further 64 hours (a total of 71 hours). After cooling to room temperature, the solvent was removed under reduced pressure at 25-30 °. The oily residue was dried for 2 hours at room temperature in a high vacuum and then chromatographed on 200 g of silica gel (230-400 mesh), solvent mixtures of ethyl acetate / petroleum ether (1: 1 parts by volume) to pure ethyl acetate being used as the eluent.

f) 351.2 mg of the partially hydrolyzed material, which contained large amounts of impurities, and 571.5 mg (62%) {3S- [3aa, 4a (IE, 3 * R) 5β, 6aa]} - hexahydro-3- fluoro-5-hydroxy-4- (3-hydroxy-4,4-dimethyl-1-octenyl) -2H-cyclopenta [b] furan-2-one (oil) was obtained. The partially hydrolyzed material (351.2 mg) was subjected to similar reaction conditions (acetic acid, water) for 42 hours and provided 39.6 mg (4.3%) additional material, so that the total yield of {3 S- [3a , 3aa, 4a (1E, 3 * R), 5ß, 6aa]} - hexa-hydro-3-fluoro-5-hydroxy-4- (3-hydroxy-4,4-dimethyl-1-octenyl) -2H -cyclopenta [b] furan-2-one, a clear oil, 611.1 mg (66%).

g) 571.5 mg {3S- [3aa, 4a (IE, 3 * R) 5β, 6aa]) - hexahydro-3-fluoro-5-hydroxy-4- (3-hydroxy-4,4-dimethyl-1 -octenyl) -2H-cyclopenta [b] furan-2-one were dissolved in 20 ml of methylene chloride (freshly filtered over aluminum oxide, activity I) under argon. 2.0 ml of dihydropyran (freshly distilled over sodium) were added to the solution and then a crystal (9.7 mg) of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 30 minutes, then poured into 50 ml of saturated aqueous sodium bicarbonate solution and extracted three times with 30 ml of methylene chloride. The extracts were washed twice with 50 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude product (oil, 1.14 g) was chromatographed on 10 g silica gel with ether / petroleum ether (1: 1) and gave 797 mg (91%) {3S- [3a, 3aa, 4a (lE, 3 * R) - 5β, 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 in the form of a clear oil (mixture of the THP diastereomers). [a] "-32.46 ° in chloroform, c = 0.8780.

h) 729.2 mg {3S- [3a, 3aa, 4a (IE, 3 * R) 5ß, 6aa] -hexahydro-3-fluoro-5 - [(tetrahydro-2H-pyran-2-yl) oxy] - 4- {3 - [(tetrahydro-2H-pyran-2-y!) Oxy] -4,4-dimethyl-1-octenyl} -2H-cyclopenta [b] furan-2-one were dissolved in 10 ml of toluene (via Calcium hydride distilled) dissolved under argon. The mixture was cooled to about -70 ° and 1.25 ml of a 1.4M solution of diisobutylaluminum hydride in hexane was added dropwise. The mixture was stirred at -70 ° for 20 minutes, then 3 ml of aqueous ammonium chloride solution was added dropwise and the mixture was added to a separatory funnel with 20 ml of water and 50 ml of ethyl acetate. The very thick suspension formed on shaking was filtered through a filter aid, the residue washed thoroughly with 100 ml of ethyl acetate and the filtrate washed again once with 60 ml of a mixture of concentrated saline and water (1: 1 parts by volume) and once with 100 ml of brine. The washing solutions

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were re-extracted once with 80 ml of ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on 200 g silica gel (230-400 mesh) of the crude product (oil, 806 mg) with ethyl acetate / petroleum ether (4: 6) provided 661.5 mg (90%) {3S- [3a, 3aa, 4a (IE, 3 * R) 5β, 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 as an amorphous solid with a melting point of 58-66 °; [<x] d -12.83 ° in chloroform, c = 1.0290.

i) To 1.54 g (4-carboxybutyl) triphenylphosphonium bromide (dried in a high vacuum at 100 ° for 2 hours over phosphorus pentoxide) and 1.275 g sodium hexamethyldisilazane (distilled), 20 ml tetrahydrofuran (freshly distilled over lithium aluminum hydride) and Given 1.25 ml of hexamethylphosphoramide. The mixture was stirred at room temperature for VA hours. The orange-red suspension was added dropwise with a solution of 560.5 mg {3S- [3a, 3aa, 4a (IE, 3 * R) 5β, 6aa] -hexahydro} -3-fluoro-5 - [(tetrahydro-2H-pyran -2yl) oxy] -4- {3 - [(tetrahydro-2H-pyran-2-yl) oxy] -4,4-dimethyl-1-octenyl} -2H-cyclopenta [b] furan-2-ol added in 4 ml of tetrahydrofuran. The yellow-orange mixture obtained was stirred for 4 hours at room temperature. The reaction was stopped by the dropwise addition of glacial acetic acid (light yellow color). The majority of the solvent was evaporated under high vacuum at or below room temperature. The residue was transferred into a separatory funnel with 100 ml of ether and 100 ml of water. The aqueous phase was acidified to pH 3 with 13 ml IN hydrochloric acid. After shaking and phase separation, the aqueous phase was re-extracted twice with 70 ml ether. The organic extracts were washed twice with 70 ml of brine and dried over magnesium sulfate. After removal of the solvent, the oily residue was dried under high vacuum for 1 Vi hours, leaving 1.45 g of an oil.

This crude acid was dissolved in 10 ml of methylene chloride (fresh over aluminum oxide, activity I) and esterified at room temperature with 15 ml of a 0.25N solution of diazomethane in ether. The mixture was stirred at room temperature for 15 minutes, poured into 100 ml of semi-concentrated aqueous ammonium chloride solution and extracted three times with 100 ml of ether. The extracts were washed twice with 70 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. 1.24 g of a yellow oil were obtained. Chromatography on 100 g of silica gel with ethyl acetate / petroleum ether (3: 7,700 ml) and then ethyl acetate / petroleum ether (1: 1 parts by volume) gave 20.8 mg (3.7%) {3S- [3a, 3aa, -4a (IE, 3 * R) 5ß, 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 (73%) (5Z, 7R, 9a, l la, 13E, 15R) -7-fluoro-l 1,15-di [(tetrahydro-2H-pyran-2-yl) oxy] -16,16-dimethyl- 9-

s hydroxy-prosta-5,13-diene-l-acidic acid methyl ester (oil) as a mixture of diastereomers; [cc] d + 2.74 ° in chloroform, c = 0.9116.

Example 2

10.6 mg (7β, 9a, IIIa, 13E, 15R) -16,16-dimethyl-ll, 15-10 di [(tetrahydro-2H-pyran-2-yl) oxy] -6,9-epoxy-7 -fluoro-5-iodo-prosta-13-en-l-acidic acid methyl ester was dissolved in a mixture of 3 ml of tetrahydrofuran (freshly distilled over lithium aluminum hydride), 6 ml of glacial acetic acid and 3 ml of water under argon. The mixture was warmed to 40 ° and stirred for 19 hours. After cooling to room temperature, the solvent was removed under high vacuum at 25 °. Then 2 ml of toluene were added and the solvent was again removed under high vacuum at 25 °. The oily residue (11.2 mg) was chromatographed on thin layer chromatography plates with 20 ether. 6.3 mg (78%) (7β, 9a, 1 la, 13E, 15R) -16,16-dimethyl-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodine prosta were obtained -13-en-l-acidic acid methyl ester (oil) as a mixture of isomers.

25 Example 3

Analogously to Example 1, (5Z, 9a, 13E, 15R, 16R) -7,16-difluoro-15 - [(tetrahydro-2H-pyran-2-yl) oxy] -9-hydroxy-prosta-5.13 -diene-l-acidic acid methyl ester in (9a, 13E, 15R, 16R) -7,16-difluoro-15 - [(tetrahydro-2H-pyran-2-yl) oxy] 6,9-epoxy-30 5- iodine-prosta-13-en-l-acidic acid methyl ester transferred.

Example 4

In analogy to Example 2, (9a, 13E, 15R, 16R) -7,16-difluoro-15 - [(tetrahydro-2H-pyran-2-yl) oxy] -6,9-epoxy-5-35 iodine- Prostate-13-en-l-acidic acid ester in (9a, 13E, 15R, 16R) -7,16-Difhior-l 5-hydroxy-6,9-epoxy-5-iodine prosta-13-en-1 Acid-methyl ester transferred.

Example 5

40 In analogy to Example 1, 1 IR, 16,16-trimethyl-7-fluoro-15R- (2-tetrahydropyranyloxy) -9S-hydroxyprosta-cis-

5-trans-13-diene acid methyl ester in (9S, 11 R, 13E, 15R) -

11,16,16-Trimethyl-15- (2-tetrahydropyranyloxy) -6,9-epoxy-7-fluoro-5-iodine prosta-13-en-1-acidic acid methyl ester.

45

Example 6

In analogy to Example 2, (9S, 11 R, 13E, 15R) -11,16,16-trimethyl-15- (2-tetrahydropyranyloxy) -6,9-epoxy-7-fluoro-5-iodine prosta-13 -en-1-Acid methyl ester in (9S, 11 R, 13E, 15R) -50 11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-5-iodine prosta-13 -en-1-Acid methyl ester transferred.

b