FR2515644A1 - 7-FLUORO 9-HYDROXY PROSTA-5,13-DIEN-1-OIC ACID DERIVATIVES - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS NEW DERIVATIVES OF 7-FLUORO 9-HYDROXY PROSTA-5,13-DIEN-1-OIQUE ACID. THE COMPOUND OF THE INVENTION MEETS THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH: R IS A HYDROGEN, A METHYL OR A FLUORO; GOLD FORM AN ELIMINABLE ETHER PROTECTIVE GROUP; R IS A LOWER ALCOHYL; R IS A HYDROGEN, A METHYL OR -OR, AND R IS A HYDROGEN, A FLUORO, A TRIFLUOROMETHYL OR A METHYL, PROVIDED THAT WHEN R IS A TRIFLUOROMETHYL, R IS A HYDROGEN OR A METHYL.

Description

The prefect of the invention relates to new fluorochemicals

  prostacyclires, a process for their preparation, the intermediates used for this purpose and the preparations

  pharmaceutical products that contain them.

  The novel fluoro-prostacyclines of the invention have the general formula = / c H = c-_ (CH 2) 2 COOR

6 F

  Wherein one of the double bonds indicated by dotted lines is present in the 4, 5 or 5,6 position; R is a hydrogen or lower alkyl; R is methyl, hydrogen or hydroxy; R 2 is hydrogen, methyl or fluoro; and R 21 is hydrogen, fluoro, trifluoromethyl or methyl; with the precision that when R 21 is a trifluoromethyl, R 2 is a hydrogen

or a methyl.

  The invention also relates to their salts, antipodes

  pharmaceutically acceptable optics or racemates.

  A preferred aspect of the invention relates to the compounds of formula

CHH-CH2-CH 2-C-OR

Ov-F o = _ F il -A

CH = CH-CH-CH 2 -CH 2 -CH 2 -CH 3

12 2 2 2 3

OH R

1 2 21

  R, R, R and R 21 are as above.

  In another aspect, the invention relates to compounds of formula

CHCH-CH 2 -CH 2-C-OR

= F 2

  R 21-HC Hz CH-CH-C-CH 2 -CH 2 -CH 2 CH 3 R 1 R 2 R 2

  R, R, R and R are as above.

  As used herein, the term "lower alkyl" includes straight and branched chain alkyl groups having 1 to 7 carbon atoms such as methyl and ethyl as also used herein, the term "lower alkanoic acids" includes alkanoic acids having 1 to 7 carbon atoms such as formic acid and acetic acid. As used herein, the term "halogen" or "halo" is used unless indications

  contrary, includes fluorine, chlorine, bromine and iodine.

  "Alkali metal" includes all alkali metals as

  lithium, sodium and potassium.

  In the process of the invention, all compounds having one or more asymmetric 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 the invention by well-formed processes. known specialists after which we can get the

  subsequent products in the form of optical enantiomers

  At the same time, the enantiomer op-

  claimed to be active or the racemates of formula I may be produced according to the optical form of the

  Formula II used as starting material.

  In the graphical representation of the compounds given throughout the present application, a thickening line (7) indicates a substituent which is in the beta orientation (above the plane of the molecule), a hatched line (and // /) indicates a substituent that is in the alpha orientation (below the plane of the molecule) and a wavy line (indicates a substituent that is either alpha or beta, or mixtures of these isomers. understand that representations

  graphs of the compounds given throughout the description

  are presented for convenience and should be understood to include other forms, including enantiomers and racemates, and not limited to

particular form presented.

  As used herein also, the term "aryl" denotes mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc., which may be unsubstituted or substituted in one or more positions with a lower alkyl nitoyl, a nitro, halo, lower alkyl, or lower alkoxy substituents, and the like, such as riaphthyl, anthryl, phenanthryl, azulyl, etc., which may be unsubstituted or substituted by or more of the groups mentioned above. The preferred aryl groups are substituted and unsubstituted mononuclear aryl groups, particularly phenyl. The term "acid catalyzed cleavage ether protecting group" refers to any ether

  which, by acid catalyzed cleavage, gives the hydroxy group.

  A suitable ether protecting group is, for example, the

  Tetrahydropyranyl ether or 4-methyl-5,6-dihydro-2H-

  Other pyranyl-ether are arylmethylethers as

  benzyl-, benzyhydryl or tritylether or alpha-

  lower alkoxy-lower alkyl-ethers, for example methoxymethyl ether or allyl ethers, or

  tri (lower alkyl) silyl ethers such as trimethylsilyl

  Ether or dimethyl tert-butyl silyl ether The preferred ethers which are removed by acid catalyzed cleavage are t-butyl, tetrahydropyranyl and tri-lower alkyl.

  silyl ethers, especially dimethyl tert-butyl ether.

  Acid-catalyzed cleavage is effected by treatment with a strong organic or inorganic acid. Among the preferred inorganic acids are mineral acids such as sulfuric acid, hydrohalic acids and the like. Among the preferred organic acids are lower alkanoic acids such as acetic acid; paratoluenesulphonic acid, etc. Acid catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent medium When an organic acid is used, the organic acid can be the solvent medium In the case of t-butyl Generally, an organic acid is used with the acid forming the solvent medium In the case of tetrahydropyranyl ethers, the cleavage is generally carried out in an aqueous medium. When this reaction is carried out, the temperature and the pressure are not critical and this reaction can take place at room temperature and

the atmospheric pressure.

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

CH-CH-CH-CH 2 O

1-Ai CH 3

F 1 H

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

OH 15 H CH 3

O

CH-CH -CH -CH O

F 1 -A Hi

CH = CHCWCH-CH 2 -CH 2 -CHI -CH 3

F 2 22

  ## STR2 ## ## STR2 ##

CH OH CH 2 23

OH -CH

CC 2 2 H 2-LOR

F l 1 1-Ailii

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

  Where R is lower alkyl in the compound of formulas IAi, I-Aii, I-Aiii and I-Aiiii, R is from

  preferably a methyl or an ethyl.

  The compounds of formula I are prepared from a compound of formula o

(H-C-C-CCR 21

-.CH = CH-CH-C-CH 2 -CH 2 -CH 2 -CH 3

z 1 OH 12

R O

he

R 1 R 2 21

  o R, R 2 and R are as above, or their

  optical antipodes or racemates,

  medias IV to XII; R 21 and CH = CH-CH-CH 2 -CH-CH 2 -CH 3

41 2 2 23

-R R

R 21 V

  K II II II CH = CH-1 CH -C -CH-CH 2-CH -CH

2 2 2 3

OR 4 R 2

R 21 VI

R

- CH = CH-CH -C-CH-CH 2 CH -CH

R ORR

  u e -vi z 1 c HO z HO 9 HO 9 HO D H: 5-HO = HO T 7, m j uc) -? - ZHDz HO & HO-HO H 0 x ix x xi H HO c 9 z z Z 1 tr 1

HO HO HO HO-0 HO-HD = HO

1 10

  -r ZH 9 zz 1 uooo HO HO HO-HD = H: DH il H z VHO -1-0 E zz 1 HO HO HO ZHD O Ili-1,10 = 11 JT zm HO IIIA u HO z E zz 1 HO HO HO-'O o-HO-HD = HO -iz of IIA Z: i 1 1 - 9 S b S 2

2 5 6 4 4

cil -cil -CH '-Cil _, -ort

2 2 2

F XII R 21

CH = CH-CH-CHCHCH

1 2 2 2 2 3

OH R

CH-CH 2 -CH 2 -CH 2 -6-, 6

F 7 Z. R?

CH = CH-CH-CCHCH

12 2 2 2 3

-6H R

H CH = CH-CH, -CH 1011

2 2 6

F xiv R 21

CHCH-CH-C-CH 2-CH 2 -CH 2-CH 3

__ 12 OH R

CH-CE 2-CH-CH-LH

2 2 R 21 xv .o CH = CH -c -CH -CH -CH

2 2 2 3

  2 CH = CH-CH-CH-CH-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 and R 21 are as above, R 11 is hydrogen, methyl or OR; -OR forms an acid-catalyzed cleavage-removing ether protecting group; R 6 is a

  lower alkyl; X is a halogen; and R 5 is a tri (alkyl)

  the lower) silyl. The compound of formula II is converted into a compound of formula IV by conventional etherification to protect the hydroxy groups optionally present in the compound of formula II. When R 1 is hydroxy in the compound of formula II, this etherification converts the hydroxy group into The preferred ethers for use in this reaction are tetrahydropyranyl and dimethyl-t-butyl-silyl-ether. To achieve this reaction, any conventional method of etherifying the Formula II to Form the Compound of Formula IV When tri (lower alkyl) silyl ether is desired, a tri (lower alkyl) chlorosilane is used as the etherifying agent in the presence of an organic base such as imidazole or pyridine

  can use any conventional organic amine base

only to drive this reaction.

  The compound of formula IV is converted to the compound of formula V by first enolising the compound of formula IV and then treating the compound of formula IV with a trialkyl halosilane.

  a typical enolization process to achieve this reaction.

  Among the preferred methods, the compound can be treated

  of formula IV with a non-aqueous alkali metal base.

  The preferred base for use in this reaction

  is lithium diisopropylamide or hexamethyl-

  Sodium disilazane To conduct the reaction using the nonaqueous alkali metal base, temperatures generally ranging from -70 to -30 o are generally preferred.

  In this case, there is an organic following iner Ge.

  Any conventional inert organic solvent which is a liquid at the above-mentioned temperatures can be used. Among the preferred solvents there may be mentioned tetrahydrofuran. The enolate of the compound of formula IV in the form of its alkali metal salt is converted into a compound. of formula V by treating the compound of formula IV

  with a trialkyl-halosilane, preferably trimethyl-

  Generally, this reaction takes place at the same temperatures and in the same solvent used to

form the enolate.

  The compound of formula V is converted into a compound of formula VI by treating the compound of formula V with a fluorinating agent. Any conventional fluorinating agent may be used to carry out this reaction. Among the preferred fluorinating agents, mention may be made of difluoride xenon, gaseous fluorine, etc. Generally, this reaction is conducted in the presence of an inert organic solvent can be used

  any conventional inert organic solvent for

  This is one of the preferred solvents.

  include halogenated hydrocarbons such as methyl chloride

  ene, carbon tetrachloride, etc. In conducting this reaction, the temperature and pressure are not

  criticisms and this reaction can take place at

  While ambient temperature can be used, it is preferred to conduct this reaction at a low temperature, i.e., between -10.degree. C. and 100.degree. C. when the compound of formula V is converted. to a compound of formula VI, the compound of formula VI is produced in the form of a mixture of the following compounds:

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  1 3 VI-A R 21 -l CH = CH-CH-CH-CH-CHCH

R 11 E 412 2 2 2 3-

OR R and A-ii F

= R 21 VI-B

CH = CH-CH-C-CH -CH-CH-CH 3

OR R R il 2 21

  o R, R and R are as above.

  The compounds of formulas VI-A and VI-B can be

  separated by conventional methods such as by chromatography.

  On the other hand, the compound of formula VI can be used as a mixture of compounds of formulas VI-A and VI-B throughout the remainder of the reaction or, if desired, to be separated at a later stage of the reaction. reaction to produce the compound of formula I having the desired fluoro orientation in position 7. If the compound of formula VI is separated into the compounds of formulas VI-A and VI-B, this same configuration of the fluorine atom is transported throughout the remainder of the reaction Thus, if the compounds of formula I are desired, the fluorine atom is in the beta position, the compound of formula VI-A is used in the remainder of the reaction scheme producing the compounds of formulas VII to XVI, the fluorine atom presented in these formulas being in the beta position. If compounds of formula I are desired where fluorine is in the 7-alpha position, the compound of formula VI-B is used in the reaction scheme. to produce the compounds of formulas VII to XVI, o the fluorine atom presented is in

alpha position.

  On the other hand, the compound of formula

  VI without separating it into the compounds of formulas VI-A and VI-B.

  In this way, the compounds of formula I are produced where fluorine is both in the alpha and beta positions through the intermediates of formulas VII to XVI having

  the fluoro group in the same position as presented.

  When the compound of formula II is converted into a compound of formula VI, it is generally preferred to use tri (lower alkyl) silyl ethers as hydroxy protecting groups. In the conversion of compounds of formula VI to compounds of formula I, it is generally preferred to protect One or more of the hydroxy groups with a tetrahydropyranyl ether On the other hand, the silyl ethers or any other conventional ether may be used in the remainder of this process.

  according to the preferred embodiment, the silyls are hydrolyzed.

  ethers of formula VI to produce the compound of formula VII which is then re-etherified to produce the compound of formula VI where the ether group is tetrahydropyranyl Any conventional hydrolysis method of ethers may be used to effect the conversion of the compounds of formula VI to compounds of formula VII and any conventional etherification process may be used to convert compounds of formula VII to compounds of formula VI. With tetrahydropyranyl as a protecting group in the compound of formula VI, It is not necessary to hydrolyze the compound of formula VI to a compound of formula VII because the compound of formula VIII can be produced directly at

from the compound of formula VI.

  The compound of formula VII is converted into a compound of formula VIII by treating the compound of formula VII with a

  reducing agent By carrying out this reaction, it is possible to use

  any conventional reducing agent that selectively reduces

  The preferred reducing agents are hydrides, in particular

  aluminum hydrides such as alkali metal hydride

  nium, and borohydrides such as metal borohydrides

  alkali, with diisobutyl aluminum hydride being

  It is also possible to conduct this reaction

  using di (branched-chain lower alkyl) -

  boranes such as bis (3-methyl-2-butyl) borane.

  this reaction, the temperature and the pressure are not

  not critical and we can drive the reaction to the temperature

  ambient temperature and at atmospheric pressure or at

  temperatures and pressures increased or decreased

  In general, it is preferred to conduct this reaction at a temperature of

  This reduction reaction can be carried out in the presence of an inert organic solvent.

  use any inert organic solvent while

  In this reaction, preferred solvents include dimethoxyethylene glycol, and ethers such as

  tetrahydrofuran, diethyl ether and dioxane.

  The compound of formula IX is obtained from the compound of formula VIII by reacting the compound of formula VIII with phosphonium salts of formula

R O

RP l H CCHCCHC -OH

2 2 2 2 X-

  R 1 RC or R 1, R 9 represent aryl or di (lower alkyl) amino; and Y is a halogen, by a conventional reaction of the Wittig type.

  any of the classical conditions in the reactions

  Wittig to perform this reaction. The compound of formula IX can be converted into a compound of formula X by esterification with diazomethane

  or a reactive derivative of a lower alkanol such as a halogen

  It is possible to use any lower alkyl

  which of the conventional conditions used in these esterification reactions to form the compound of formula X to

from the compound of formula IX.

  The compound of formula X is converted into a compound of formula XI by treating the compound of formula X with a halogenating agent. Among the preferred halogenating agents are N-halosuccinimides, in particular N-iodosuccinimide.

  conduct in the presence of a polar solvent such as acetone

  nitrile and halogenated hydrocarbons such as methylene chloride, ethylene chloride, etc. In fact, one can

  use any conventional polar organic solvent

  that when conducting this reaction, one can use

  temperatures ranging from 0 to 35 C.

  This reaction should be carried out at room temperature.

  The compound of formula XI is converted into a compound of formula XII by hydrolysis of ether. Any conventional ether hydrolysis process may be used to conduct this reaction.

  a mild acid hydrolysis as with aqueous acetic acid.

  In the next step, the compound of formula XII is treated with a dehydrohalogenating agent to produce the compounds of formulas XIII and XIV mixed.

  reaction, any dehydrating agent can be used

  Among the preferred dehydrohalogenating agents, mention should be made of diazabicycloalkanes or

15644

  alkenes such as 1,8-diazabicyclol 5 4 O lundec-7-ene and

  In addition, it is possible to use 1,4-diazabicyclol 2 2

  yer any other classic organic base used

  for dehydrohalogenation to drive this reaction.

  This reaction produces the compounds of formula XIII and the

  mixed compounds of formula XIV can be separated into

  salts of formula XIII compounds of formula XIV by any

  what a classic process like chromatography.

  The compound of formula XIII is converted into a compound of formula XV and the compound of formula XIV into a compound of formula XVI by hydrolysis. Any conventional method of ester hydrolysis can be used to conduct these reactions. ester hydrolysis, either the compound of formula XIII or the

  compound of formula XIV with an alkali metal hydroxide.

  Among the preferred alkali metal hydroxides used in this reaction are sodium hydroxides

and potassium.

  In the practice of the invention, it is possible to use

  which basic pharmaceutically acceptable salt of the compound of formula I where R is hydrogen. Among the preferred pharmaceutically acceptable basic salts are alkali metal salts such as lithium, sodium and

  potassium, sodium being particularly preferred.

  Other salts which are also preferred are alkali metal salts such as calcium and magnesium, amine salts such as lower alkylamines, e.g.

  ethylamine and lower alkyl-hydroxy amine salts

  substituted and tris (hydroxymethyl) aminomethane Ammonium salts are also preferred. Among the other salts it is necessary to

  dibenzylamine, monoalkylamines or dialkyl

  amines and salts with amino acids (eg salts

with arginine and glycine).

  Among the preferred compounds of the invention are compounds of formulas XIII and XV where R and R are

both are hydrogens.

  The compounds of formula I, their pharmaceutical salts,

  acceptable as well as their optical and racial antipodes

  mates are useful as anti-secretory agents, anti-hypersensitivity

  tensors, anti-ulcerogens and to fight the hyper-acidity

  gastric acid, as well as as agents against agglutination.

blood platelets.

  Prostacyclines of formula I of the invention are shown to be

  are active as anti-agglutination agents

  blood platelets by the administration of methyl ester

  of the acid (5Z, 7B, 9 ", 11a, 13E, 15R) -7-flu Gro

  6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-

oique according to the following experience.

  30 ml of blood is drawn into the jugular vein of a conscious beagle using 2 x 15 ml Vacutainer tubes,

  without additive, connected to a needle for

  25.4 mm weighing 20 g The blood was immediately transferred to a 50 ml conical plastic centrifuge tube containing 3 ml of 3.8% sodium citrate (3.8 g of sodium citrate crystal, Na 3 C 6 H 507 2 H 20, in 100 ml

  of distilled water), gently close and mix

  pump the 160 grams of citrated blood for 15 minutes at 20 ° C.

  Carefully fold the platelet-rich plasma (PRP) with a pipette, without disturbing the buffy coat and the erythrocyte layer. PRP is placed in plastic tubes.

  16 x 125 mm, close and keep at room temperature

  biante, 19-21 DC The preparations of PRP presenting

  a shade of redness, indicating hemolysis

  the remaining blood, after removing the PRP, at a

  900 g for 10 minutes, to give platelet-poor plasma (PPP). The PRP is used immediately and the agglutination study is completed in all three

hours after preparation.

* Agglutination of platelets with a module is measured

  double-channel agglutination system linked to a

  two-point recorder to continuously record the increase in light transmission due to platelet clumping.

  0 to 100% transmission with PRP (0%) and PPP (100%).

  The temperature is adjusted to 37 and the stirring speed to 900 rpm. 0.45 ml of PRP is added to a cuvette containing a Teflon-coated stir bar and preheated.

  at 37 in a water bath We add 5 p 1 of various

  centers of the methyl ester of the acid (5 Z, 7 6, 9 ea, 11 i-

  13 E, 15 R) -7-fluoro-6,9-epoxy-11,15-dihydroxy-1-, 16-

  dimethyl-prosta-5,13-dien-1-ol, diluted from a solution of

  5 x 10 M stock in DMSO (dimethylsulfoxide) with a phosphate buffered saline containing 1 mg / ml of beef serum albumin, fraction V, and stirred for 1 minute. inducer of agglutination, arachidonic acid,

  a concentration that can cause agglutination at 50-

  % after 5 minutes The percentage of inhi-

  bition, presented in the following table, from the ratio of the percentage of agglutination with the methyl ester of

  (5Z, 6,9a, 11 ", 13E, 15R) -7-fluoro-6,9-epoxy-11,15-acid;

  dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-olque to that

that we have with the vehicle x 100.

  Methyl ester concentration of the acid

  (5Z, 7B, 9O, 11ac, 13E, 15R) -7-fluoro-6,9-epoxy-

  11,15-dihydroxy-16,16-dimethyl-prosta-5,13-

  dien-1-oic% inhibition I x 1013 M 14.2 3 x 10-13 M 20.8

-1 20,

  x 10-12 M 71.4 1 x 10-11 M 57.8 1 x 10-10 M 20.8

  The preparation of phosphate buffered saline

  te and arachidunic acid solucion ut-iise above

  is carried out as follows: the physiological salt is prepared

  phosphate solution (PBS) by adding a 1 mM solution of aqueous sodium phosphate buffer, pH 7.4 to 0.85% by weight.

  weight / volume of an aqueous solution of sodium chloride.

  The arachidonic acid solution is prepared as follows: A stock solution of 10 mg / ml in absolute EtOH is prepared

  and keep it in a freezer To prepare a solution

  10 ml, 0.3 ml of the stock solution are evaporated to near dryness under nitrogen and redissolved in 0.75 ml of 0.02 M NH 4 OH (prepared) and 0.2 ml of PBS on. performs additional dilutions of arachidonic acid

  with a mixture of NH 40 H and PBS.

  The compounds of formula I or their

  pharmaceutically acceptable salts in various preparations

  In these preparations, the novel compounds are administrable in the form of tablets, pills, powders, capsules, injectable solutions,

  suppositories, emulsions, dispersions, and under

  Suitable forms The pharmaceutical preparations which contain the compounds of formula I are formed

  conveniently by mixing with an organic carrier, pharmaceutically

  Non-toxic tick or a non-toxic pharmaceutical inorganic carrier. Typical pharmaceutically acceptable carriers include, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline,

  and other conventional pharmaceutically acceptable carriers

  The pharmaceutical preparations may also contain non-toxic auxiliary substances such as emulsifying agents, preservatives and wetting agents, etc., such as, for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylenesorbitan, dioctylsodium sulfosuccinate, etc. The daily dose administered for the compounds varies naturally with the particular new compound used because of the very potency of the compounds, with the fashion

  chosen administration and the size of the organism

  The dose administered is not subject to defined limits but is usually in the amounts

  effective pharmacological function of prostacyclin.

  Oral administration is representative of a typical method of administering prostacyclin compounds of formula I. By this route, prostacyclines of formula I can be administered at a dose of 0.1 microgram to 0.30 microgram.

  per day per kilogram of body weight.

  The following examples specify the invention without the

  In the examples, the ether used is diethyl ether. All temperatures are in degrees Celsius.

  The petroleum ether used in the examples has a boiling point of between 35 and 60 ° C. In the examples,

"h" indicates the hours.

Example 1

  1, 1, 3 R * 1, 3 m, 1H, 3 R * 1, 5,6 Alll-hexahydro-5-ll (1,1-dimethyl)

  ethyl) dimethylsilyloxy-4-lll 3- (1,1-dimethylethyl) dimethyl

  silylloxyl-4,4-dimethyl-1-octenyl-2H-cyclopentalblfuran

  2-one. 502.2 mg (1.69 moles) of 1 to 3 Rl 3 aa, 4 o (1 E, 3 R *), B, 6 acll-hexahydro-5-hydroxy-4- (3-hydroxy) are dissolved -4,4-dimethyl-

  1-octenyl) -2 H-cyclopenta Eblfuran-2-one in 15 ml of dimethyl

  formamide (reagent grade, dried over 3 A molecular sieves) under positive argon pressure 1.045 g

  (6.93 m Moles = 4.09 eq) of t-butyldimethylchlorosilane (

  before use) and 587.6 mg (8.63 m Moles = 5.09 eq) of imidazole (reagent grade) The resulting mixture was stirred at room temperature for 18 h, poured into 60 ml of 0.5N aqueous HCl ice-cold and extracted 3 times with 60 ml of diethyl ether The extracts are washed with 60 ml of a mixture of saturated aqueous NaHCO 3 / H 2 O / brine = 1: 1: 2 and then washed with 60 ml of brine The extracts are combined, dried over MgSO 4 and concentrated under a reduced pressure. There remains 1.25 g of a white semi-solid. The crude product is chromatographed on a column of 75 g of silica gel. silica with 10% by volume of ether / 90% by volume of petroleum ether (first liter) followed by 20% by volume of ether / 80% by volume of petroleum ether is obtained 857.1 mg (1 , 63 m Mole, 96.4 c) from

  ## STR2 ##

  ethyl} dimethylsilylloxyl-4-lll 3- (1,1-dimethylethyl)

  dimethylsilylloxyl-4,4-dimethyl-1-octenyl-2H-cyclopenta

lblfuran-2-one

  in the form of a white amorphous solid; Mp 67-68.

Example 2

  ## STR2 ## wherein R 1, 3a, 4a (1E, 3R *), 5B, 6, acll-4,5,6,6a-tetrahydro-5-ll

  dimethylethyl) dimethylsilyloxy-4-lll 3- (1,1-dimethyl)

  ethyl) dimëthylsilylloxyl-4,4-dimethyl-octényll-2- (tri-

  methylsilyl) oxy-3a H-cyclopentalblfuran 570 pl (4.07 moles) of diisopropylamine (distilled from Ca H 2) are dissolved in 15 ml of tetrahydrofuran (freshly distilled from LAH). The mixture is cooled to + 3 C under positive argon pressure Added

  dropwise at + 3 C 2.5 ml (3.75 m Moles) of N-butyl

  1.5 N lithium in hexane After stirring at +3 ° C. for 5 minutes, the mixture is cooled to -40 ° C. with a dry ice / acetone bath. 1.757 g (3.35 moles) are added dropwise. of

  1-3, 4a (1E, 3'R), 5a, 6α-hexahydro-5-ll (1, 1a);

  dimethylethyl) dimethylsilylloyl-4-lll 3- (1,1-dimethylethyl)

  dimethylsilylloxyl-4,4-dimethyl-1-octenyl-2H-cyclopenta

  lblfuran-2-one dissolved in 6 ml of THF in a solution of lithium diisopropylamide at -40 ° C. After stirring at -40 ° C. for a further minute, 570 μl (4.49 mmoles) of trimethylchlorosilane (distilled 2 minutes after the addition, the cooling bath is removed and the mixture is left

  warm to + 15 C for a period of 20 minutes.

  The solvent is removed under vacuum (approx. 0.2 mm Hg) at room temperature.

  at room temperature or below and the residue was dried under high vacuum for 15 minutes. 10 ml of ether (freshly distilled through aluminum oxide, activity I) was added under argon and the mixture was filtered through a sintered glass funnel The white residue is washed 3 times

  With 3 ml of ether, the light filtrate is concentrated under reduced pressure.

  yellowish and the oily residue is dried under a high vacuum (room temperature) for 1 hour which produces the

l 3 a R-

  ú 3 aa, 4 a (1 E, 3 * R), 5,6 aall-4,5,6,6 α-tetrahydro-5-EL (1,1-

  dimethylethyl) dimethylsilylloxyl-4-lll 3-11,1-dimethyl-

  ethyl) diméthylsilylloxyl-4,4-dimethyl-octenyll-2- (tri-

  methylsilyl) oxy-3a H-cyclopentalblfuran

Example 3

  1, 3a, 3a, 4a (1E, 3'R), 5e, 6a-1H-hexahydro-3-fluoro-5-1E (1,1-

  dimethylethyl) dimethylsilyloxy-4-lll 3- (1,1-dimethyl)

  ethyl) dimethylsilyloxy-4,4-dimethyl-1-octenyl-2H-cyclohexyl

  pentalblfuran-2-one The compound is dissolved

  l 3 a R-1 3 a L, 4 a (1 E, 3 * R), 55.6 aall-4,5,6,6 a-

  tetrahydro-5-ll-1,1-dimethyl-1-ethyl) dimethylsilylloxyl-4-

  III 3- (1,1-dimethylethyl) dimethylsilyloxy-4,4-dimethyl-1-

  octenyl-2- (trimethylsilyl) oxy-3H-cyclopentalblfuran in 15 ml of methylene chloride (freshly filtered

  through aluminum oxide, activity I) under argon.

  The mixture is cooled to + 2 ° C. with an ice bath and

  680 mg (6.8 m Moles) of potassium bicarbonate are added

  sium (dried under high vacuum at 100 over P 205 for 3 hours) followed by 632.9 mg (3.73 m Moles) of xenon difluoride while stirring. Immediate reaction then occurs as judged by vigorous evolution of gas in the first seconds following the addition of Xe F 2 The mixture is stirred at + 2 ° C. for 20 minutes, poured into 150 ml of ice water and extracted 3 times with 150 ml of methylene chloride. The extracts are washed twice with 150 ml of brine, combined, dried over Mg 504 and concentrated under reduced pressure. The residue is dried under high vacuum.

  for 18 hours leaving 1.92 g of a yellowish oil.

  The crude product is chromatographed on 200 g of silica gel (0.062-0.031 mm of mesh size) using the technique of vaporization chromatography. As elution solvents, 5% ethyl acetate is used as elution solvent. in volume / petroleum ether at 95% by volume (1 liter) followed by 10% ethyl acetate / petroleum ether. The following products are obtained in the order of elution: 1.06 g

  (1.95 m Mole) 58% of l 3 SlE 3 cc, 3 act, 4 at (E 3 * R) 53, 6 a HJ hexa-

  hydro-3-fluoro-5-1 (1,1-dimethylethyl) dimethylsilyl Joxyl-

  4-III-3- (1,1-dimethylethyl) dimethylsilyl J-oxyl-4,4-dimethyl-

  1-octenyl-2H-cyclopentalblfuran 2-one; white needles form at rest, P f 49-510; , 2 mg (0.315 mole) 9.14% of 1 3 Rl at 4 Ll, *) 53 6 (l -e ay r C 1 1

  dimethylethyl) dimethylsilyloxy-4-yl-3- (1,1-dimethyl-4-yl)

  dimethylsilyl) oxy-4,4-dimethyl-1-octenyl) -2H-cyclopenta

  Eblfuran-2-one, starting material; and 98.9 mg (0.182 m Mole) 5.14% of

  3 R-1 313.3 aa 4 ct (1 E, 3 * R), 51 F, 6 aal-hexahydro-3-fluorine O-

  5-11 (1, 1-dimethylethyl) dimethylsilyloxy-4-llllll (1, 1 2 Hcyclopentylfurafl-2-ofl;

amorphous white solid; P 83-850.

Example 14

  1 3 S-1 3 ct, 3 aax, 4 at (1E, 3 * R), 51.6 act (J) -Hexahydro-3-fluoro 5-

  hydroxy-4 - (<3-hydroxy-4,4-dimethyl-1-octenyl-11-2H-cyclopenita-

  lb) furan-2-one 1.597 g (2.9 moles) of the fluorola'stone are dissolved

  3a, 4a (1E, 3 * R), 515e, 6a, 1H-hexahydro-3-fluoro-5-ll (1,1-dimethyl) -1-

  ethylsilyl) oxy) -4,4-dimeethyl-1-octer 1 y 1 -2 H-cyclopentalbl-

  furan-2-one in 60 ml of acetic acid (reagent grade) and the mixture is heated at 55 ° C. under a positive argon pressure. 6 ml of water are added while stirring at 55 ° C. After 7 hours, 4 ml of water are added and the mixture is stirred at 55 ° C. for a further 64 hours (71 hours in total). After cooling to room temperature, the solvent is removed under vacuum (approx. 0.2 Torr) at 25.degree. The oily residue is dried under high vacuum for 2 hours at room temperature and then chromatographed on 200 g of silica gel (0.062-0.031 mm mesh size) using solvent mixtures ranging from ethyl acetate / petroleum ether 1: 1 parts in

  volume with pure ethyl acetate for elution.

  351.2 mg of partially hydrolyzed material containing large amounts of impurities and 571.5 mg (1.82 m Mole, 62%) of

  3a, 3a, 4a (1E, 3 * R), 513,6 acall-hexahydro-3-fluoro

  -hydroxy-4- (3-hydroxy-4,4-dimethyl-1-octenyl) -2H-cyclopentylfuran-2-one

  (oil) If the 351.2 mg of partial

  hydrolyzed under similar reaction conditions (HOAC, H 20) for 42 hours resulted in the formation of 39.6 mg (0.126 m Mole) 4.3%

  3a, 3a, 4 (1E, 3 * R), 613,6-hexahydro-3-fluoro-5-

  hydroxy-4- (3-hydroxy-4,4-dimethyl-1-octenyl) -2H-cyclopenta

lblfuran-2-one.

  The total return in

  3a, 3a, 3a, 4a (1E, 3 * R), 53, -

  6-hexahydro-3-fluoro-5-hydroxy-4- (3-hydroxy-4,4-hydroxy)

  dimethyl-1-octenyl) -2H-cyclopentalblfuran-2-one

  is 611.1 mg (1.94 mmol) 66%, oil, clear.

Example 5

  3a, 3a, 4a (1E, 3 * R), 553.6 aall-Hexahydro-3-fluoro-5-

  (tetrahydro-2 H -pyran-2-yl) oxyl-4-yl-tetrahydro-2H-pyran

  2-yl) oxy-4,4-dimethyl-1-octenyl-2H-cyclopentalblfuran

  2-one 571.5 mg (1.83 mole) of

  1-3, 3 aa, 4 c (1 E, 3 * R), 5 B, -

  6a) 11-hexahydro-3-fluoro-5-hydroxy-4- (3-hydroxy-4-4-dimethyl-1-octenyl) -2H-cyclopentalblfuran-2-one in 20 ml of methylene chloride (freshly filtered) through

  aluminum oxide, activity I) under a positive argon pressure.

  2.0 ml (21.9 mMol) of dihydropyran (freshly distilled from sodium) is added with stirring, followed by a crystal

  p-toluenesulfonic acid monohydrate (9.7 mg, 0.05 moles).

  The mixture is stirred at room temperature for 30 minutes and poured into 50 ml saturated aqueous sodium bicarbonate.

  and extracted 3 times with 30 ml of methylene chloride.

  The extracts are washed twice with 50 ml of brine, combined,

  dried over MgSO 4 and concentrated under reduced pressure.

  The crude product (1.14 g, oil) is chromatographed on a column of 100 g of silica gel with ether / petroleum ether (1: 1) to give 797 mg (1.65 moles). % of

l 35-l 3 a, -

  3 act, 4a (1E, 3 * R), 5,6a) 11-hexahydro-3-fluoro-5-l (tetrahydro)

  2 H -pyran-2-yl) oxyl-4-1- (tetrahydro-2H-pyran-2-yl) oxyl-

  4,4-dimethyl-1-octenyl-2H-cyclopentalblfuran-2-one in the form of a clear oil (mixture of diastereoisomers

  rlD 25 -32.46 C danz CHCl 3, c 0.8780.

D 3

Example 6

  1 3 S-1 3 a, 3 ac, 4 a (1 E, 3 * R), 5 X, 6 al) 1-Hexahydro-3-fluoro-5-

  1 (tetrahydro-2H-pyran-2-yl) oxyl-4-1- (tetrahydro-2H-pyran)

  2-yl) oxyl-4,4-dimethyl-1-oct-4'-nyll-2H-cyclopentalblfuran-2-ol After having dissolved 729.2 mg (1.51 mole) of

3 S-1 3 c, 3 aa, -

  4 ct (1 E, 3 * R), 51.6 aa 3 1-hexahydro-3-fluoro-5-l (tetrahydro-2 H-

  pyran-2-yl) oxyl-4-1-3- (tetrahydro-2H-pyran-2-yl) oxyl-4,4-

  dimethyl-1-octenyl-2H-cyclopentalblfuran-2-one in 10 ml of toluene (distilled from CaH 2) under argon, the mixture is cooled to about -70 ° C. with a bath of dry ice and acetone It is added dropwise at -70 ° C.

  1.25 ml (1.75 moles) of a 1.4 M solution of diisocyanate hydride

  butylaluminum in hexane The mixture is stirred at -70 ° C. for 20 minutes. A saturated aqueous solution of ammonium chloride is added dropwise at -70 ° C.

  transfer the resulting mixture with 20 ml of water and 50 ml of

  After stirring, a very thick slurry is formed which is filtered through celite. The residue is washed thoroughly with 100 ml of ethyl acetate. filtrate in a separatory funnel and washed once with 60 ml of brine / water (1: 1 parts by volume) and once with 1 ml of brine. The aqueous washings are reextracted once with 80 ml of sodium acetate. The organic extracts are combined, dried over MgSO 4 and concentrated under reduced pressure. The flash chromatography on 200 g of silica gel (0.062-0.031 mm mesh size) of the crude product (806 mg; ) with ethyl acetate / petroleum ether (4: 6) gives 661.5 mg (1.36 m Mole) 90% of

  3a, 3a, 4a (1E, 3 * R), 5B, 6aall-hexahydro-3-

  fluoro-5-1 (tetrahydro-2H-pyran-2-yl) oxyl-4-1-3- (tetrahydro-

  2 H -pyran-2-yl) oxyl-4,4-dimethyl-1-octenyl-2H-cyclopenta

  1-furan-2-ol as an amorphous solid, mp 58-66 ° C; lal 5 =

-12.83 C in CH C 13, c = 1.0290.

Example 7

Methyl ester of acid

  (5Z, 7R, 9a, 1a, 13E, 15R) -7-Fluoro-11,15-dil (2H-tetrahydro)

  pyran-2-yl) oxyl-16,16-dimthyl-9-hydroxyprxy-prosta-5,13-dien

  1-oi that is available in a three-necked flask under argon

  1.54 g (3.47 m Moles) of (4-carboxybutyl) triphenyl bromide

  phosphonium (dried under high vacuum at 100 over P 205 for 2 h) and 1.275 g (6.95 m Moles) of hexamethyldisilazane sodium

  (dist) 20 ml of tetrahydrofuran (freshly

  from HMA) and 1.25 ml (7.18 moles) of hexamethyl-

  phosphoramide (dist) This mixture is stirred at room temperature

  room temperature for 1 h 2 is added dropwise to the suspension

  orange red solution a solution of 560.5 mg (1.16 mole) of

l 3 S-1 3 ct, 3 aca, -

  4 1 (1 E, 3 * R), 3,6-aal-hexahydro-3-fluoro-5-1 (tetrahydro-2H)

  pyran-2-yl) oxyl-4-1-3-1 (tetrahydro-2H-pyran-2-yl) oxy-4,4-dimethyl-l-2-phenyl-2H-cyclopentalblfuran-2-ol in 4 ml of tetrahydrofuran The orange yellow mixture obtained is stirred at room temperature for 4 hours. The reaction is quenched by adding dropwise glacial acetic acid (pale yellow color). Most of the solvent is evaporated under high vacuum at room temperature. The residue is transferred with 100 ml of ether and 100 ml of water into a separatory funnel. The aqueous phase is acidified to pH 13 with 13 ml of 1 N HCl. After stirring and separation of the two phases. the aqueous phase is reextracted twice with 70 ml of ether. The organic extracts are washed twice with 70 ml of brine, combined and dried over

  Mg SO 4 After removing the solvent, the oil residue is dried

  under a high vacuum for 1 h, leaving 1.45 g of an oil This crude acid is dissolved in 10 ml of chloride

  methylene (freshly filtered through aluminum oxide

  nium, activity I) and is esterified at room temperature by addition of 15 ml (3.75 moles) of a 0.25 N solution of diazomethane in ether. After removing the solvent with a vacuum cleaner, the solution is dissolved. remaining oil (1.27 g) in ml of tetrahydrofuran and 2.8 ml (2.8 m Moles) of a 1.0 M solution of tetra-n-butylammonium fluoride

  in tetrahydrofuran. The mixture is stirred at room temperature.

  After standing for 15 minutes, it is poured into 100 ml of a semi-concentrated aqueous ammonium chloride solution and extracted 3 times with 100 ml of ether. The extracts are washed twice with 70 ml of brine. it is dried over Mg 504 and concentrated under reduced pressure to give 1.24 g of a yellow oil. Chromatography over 100 g of silica gel with ethyl acetate / petroleum ether (3: 7) ( 700 ml) followed by ethyl acetate / petroleum ether (1: 1 parts by volume) gives 20.8 mg (3.7%) of

l 3 S-1 3 a, 3 a ", -

  4 at (1 E, 3 * R), 55.6 acll-hexahydro-3-fluoro-5-l (tetrahydro-2 H-

  pyran-2-yl) oxyl-4-1-3- (tetrahydro-2H-pyran-2-yl) oxyl-4,4-

  dimethyl-1-octenyl-2H-cyclopentalblfuran-2-ol (starting material) and 496.3 mg (0.85 m Mole) 73% methyl ester of the acid

(5Z, 7R, 9a, 11a, -

  13E, 15R) -7-fluoro-11,15-dil (tetrahydro-2H-pyran-2-yl) oxyl-

  16,16-dimethyl-9-hydroxy-prosta-5,13-dien-1-ol (oil) as a mixture of diastereoisomers; ClalD + 2.74 in CH C 13, c = 0.9116.

Example 8

Methyl ester of acid

  (7D, 9a, 11a, 13E, 15R) -16,16-Dimethyl-11,15-dil (tetrahydro-

  2 H -pyran-2-yl) oxyl-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en

1-oï that.

  246.9 mg (0.424 m mol) of methyl ester of the acid are dissolved

(5Z, 7R, 9, 11a, 13E, 15R) -7-

  fluoro-11,15-dil (tetrahydro-2H-pyran-2-yl) oxyl-16,16-

  dimethyl-9-hydroxy-prosta-5,13-dien-1-oic in 10 ml of acetonitrile (dried over 3 A molecular sieves) under a positive argon pressure 476.9 mg (2.12 m Moles, 5 eq) of N-iodosuccinimide while stirring, the flask is swept with argon, closed with a plug and wrapped in aluminum foil to protect the reaction mixture from light. The mixture is stirred at room temperature for 27 hours, poured into 100 ml of a 10% w / v solution of sodium thiosulphate in water.

  and 3 foils are extracted with 100 ml of methylene chloride.

  The organic extracts are washed twice with 100 ml of brine, combined, dried over MgSO 4 and concentrated at a pressure given by a vacuum. 285.9 mg of an oily residue are obtained. Chromatography on 75 g of gel silica with ether / petroleum ether (1: 1 parts by volume) gives 186.8 mg (0.263 m Mole) 62% of methyl ester of the acid

  (7,9a, 11,13E, 15R) -16,16-dimethyl-11,15-

  dil (tetrahydro-2H-pyran-2-yl) oxyl-6,9-epoxy-7-fluoro-5-iodo

prosta-13-en-lo that

  (oil) as a mixture of diastereoisomers.

Example 9

Methyl ester of acid

  (7.9a, 11c, 13E, 15R) -16,16 'Dimethyl-11,15-dihydroxy-6,9-

  epoxy-7-fluoro-5-iodo-prosta-13-en-1-oue

  10.6 mg (15 Pmoles) of the methyl ester of the

cide

  (71.9 L, 11 E, 13 E 115 R) -16,16-dimethyl-

  11,15-dil (tetrahydro-2H-pyran-2-yl) oxyl-6,9-epoxy-7-

  fluoro-5-iodo-prosta-13-en-1-oic in a mixture of 3 ml of tetrahydrofuran (freshly distilled from LAH), 6 ml of glacial acetic acid and 3 mml of water under a pressure of Positive argon The mixture is heated in an oil bath at 400 ° C. and stirred for 19 hours. After cooling to room temperature, the solvent is removed under high vacuum to 2 ml of toluene and the solvent is removed. Under a high vacuum at 250 ° C the oily residue (11.2 mg) was chromatographed on a thin layer of silica gel with ether to give 6.3 mg (11.65 Moles, 78%) of methyl ester of

  (7B, 9, 1α, 13E, 15R) -16,16-dimethyl-11,15-dihydroxy-

  6,9-epoxy-7-fluoro-5-iodo-prosta-13-n-1-oo

  (oil) as a mixture of isomers.

Example 10

Methyl ester of acid

  (5 Z, 713, 9a, 11a, 13E, 15R) -7-fluoro-6,9-epoxy-11,15-dihydroxy-

  16.16-dimethyl-prsta-5,13-di 6 n-1-o'iue 6.3 mg (11.66 P Moles) of methyl ester of the acid are dissolved

(713.9c, 11c, 13E, 15R) -16,16-

  dimethyl-1,1,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-

  13-en-1-oic (mixture of isomers) in 2.0 ml of toluene (distilled from Ca H 2) under a positive argon pressure. 20 μl (134 μ moles) of diazabicyclol 5 Lundec-7-ene (distilled from Ca H 2) With stirring, the mixture is slowly heated to 90 ° C. (for 90 minutes) and kept at 90 ° C. for 22 hours. After cooling to room temperature The mixture is poured into 75 ml of

  semi-saturated brine and extracted 3 times with 20 ml of ether.

  The extracts are washed once with 20 ml of brine, combined, dried over MgSO 4 and concentrated at a given pressure by an aspirator. The remaining oil is dried under a high vacuum for 3 h and the 6 is chromatographed. 2 mg of residual oil on a silica gel thin layer with ethyl acetate Two products are isolated: 3.0 mg (7.27 mol) 62% of methyl ester of the acid

<5 z 7, -

  9a, 11a, 13E, 15R) -7-fluoro-6,9-epoxy-11,15-dihydro XY-16,16-

  dimethyl-prosta-5,13-dien-1-o; that (oil) and 1.1 mg (2.66 p Moles) 23% of methyl ester of the acid

  (4E, 6a, 73, 9a, 11a, 13E, 15R) -7-

  fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prostacyclin

4.13-dien-1-oic (oil).

2 515644

Example i 11

Sodium salt of acid

  (5Z, 7l3.9ct, 11a (, 113E, 15R) -7-Fluoro-6,9-e-poxy-11,15-dihydroxy-

  3.0 mg (7.27 moles) of methyl ester of the acid are dissolved

  (5Z, 7f3, 9c, 11t, 13E, 15R) -7-

  fluo-69-oxyl, 15-dihydroxy-16,16-dimethyl-prosta-.

  In a mixture of 0.5 ml of methanol and 0.5 ml of water under argon, 73 μl (7.3 μl Moles 1 eq) of 0.1 N sodium hydroxide are added and the mixture is shaken. the mixture at room temperature for 2 h. The methanol is removed at reduced pressure and the remaining aqueous solution is lyophilized to give the sodium salt of the acid Z, 7.9 z 11 c 1315.

7-Fluoro-6,9-epoxy-11,15-dihydroxy-16,16 dimethyl prosta-.

  13-dien-1 lo in the form of a white powder; Pl 48-510 C.

Example 12

  ## STR2 ## ## STR3 ## wherein ## STR1 ## wherein ## STR2 ## is a compound of the formula ## STR2 ## wherein R 2 is Hexahydo 4-1 EI 3- (1-dimethylethyl) dimethylsilyl-4-chloro-1-ocotenyl; By the method of Example 1, the following procedure is carried out: ## STR5 ##

  4 R *) 6 aa) 1-hexahydro-4-fluoro-3-hydroxy-1-octenyl) -2H-

cyclopentalblfuran-2 one

in I 3 to Rl 3 ac, 4 to L-

  (1E, 3R *, 4R *) 6a (J) -hexahydro-4- (4H) -1- (1,1-dimethylethyl) -

  dimethylsilyloxy-4-fluoro-1-butenyl) -2H-cyclopentalby -

-35-

f ur an-2-one.

Example 13

  2 H-cyclopentalb) furani-2-one By the method of Examples 2 and 3, the

L 3 a R-1 3 act, 4 a-

  dimethylsilyl) oxy-4-fluoro-1-octenyl-2H-cyclopentalb J-

  furan-2-one in 1 to 3 R-1 3 act, 4 at (E, 3 R *, 4 R *) 6 acal

  3-hexahydro-4-fluoro-4- (1,1-dimethyl-Lethyldi) dimeethyl-

  silyloxy-4-fluoro-1-octenyl-2H-furan-2-one.

Example 14

  ## STR2 ## in the process of Example 14, the reaction is carried out by means of the procedure of Example 14, and the reaction is carried out with the aid of the procedure described in US Pat.

(3 a R-1 3 aci, 4 a <1 E, 3 R *, -

  4 R *) 6 aa-1-hexahydro-3-fluoro-4-1 El 3 (1,1-dimethylethyl) -

  dime / thylsilyloxy) -4-fluoro-1-octenyl-2H-cyclopentaf

  furan-2-one in l 3 a R-1 3 aa, 4 cx IE, 3 R *, 4 R *) 6 ac LJ

  hexahydro-3-fluoro-4- (3-hydroxy-4-fluoro-1-octenyl) -2-H-

cyclopenitalb J furan-2-orne.

  Ex Emple 15 l 3 Rlax 4 (E 3 * 4 * 6 c LI Hxhdo 3 fur 3

  1 (Tetrahydro-2H-pyran-2-yl) oxy) -4-fluoro-1-octenyl-2-yl

  cyclopentalb J furan-2-one By the method of Example 5, the

3 a R-1 3 act, 4 a <1 E, 3 R *, -

  4 R) atlheayr fur 3-hydroxy-4-fluoro-1-

  octeenyl J-2H-cyclopentalb) furan-2-one in

  ## STR5 ## wherein: ## STR2 ##

  1 (tetrahydro-2H-pyran-2-yl) oxy-4-fluoro-1-octenyl-2-yl

-36-

cyclopentalbj f uran-2 -onia.

Example 16

  l 3 Rlax 4 (E 3 * 4 * 6 ccl Hxhdo 3 fur 3

  1 tetrahydro-2H-pyran-2-yl) oxyl-4-fluoro-1-octenyl-1H-H

  cycl cyclopentaf blfutran-2-ol By the method of Example 6, transform the

1 3 R-1 3 aca, 4 a <1 l E, 3 R *, -

  4 R) atlheayr lur- <3 ltetrahydro-2 H-pyran

  2-yl) oxy) -4-fluoro-1-octenyl) -2H cyclopentatb) furan-2-one

  in 1 to R-3 aa, 4 a <(1 E, 3 R *, 4 R *) 6 aa) I -hexahydro-.

  3.-Fluoro-4-E 3 -El (tetrahydro-pyran-2-yl) oxyl-4-fluoro-1-

  octenyll-2H-cyclopentalblfuran-2-ol.

Example 17

Methyl ester of acid

  (5 Z, 9 a L, 13 E, 15 R, 16 R) -7,16-Difluoro-15-l (tetrahydro-2H-pyzfan)

  2-yl) oxy-9-hydroxy-5,13-die 6 n-1-oij By the method of Example 7, the

l 3 a R-1 3 act, 4 ct <E, 3 R *, -

  4 R *) 6-O-hexahydro-3-fluoro-4-yl-1 (2-tetrahydro-2H-pyranediol)

  2-yl) oxyl-4-fluoro-1-octenyl-2H-cyclopentalb) furan-2-01 to the acid methyl ester <5Z, 9g, 13E, 15R, 16R) -7, 16 difluoro 15

  E <tetrahydro 2 H -pyran-2-yl) oxyl-9-hydroxy-prosta 5,13-

  dien-1-oic acid. Exe mple 18 Methyl ester of acid

  (9 to 513 E, 15 R, 16 R) -7,16-Difluoro-15-E (tetrahydro-2H-pyran-2-one)

  yl) oxy) -6,9-epoxy-5-iodo-prosta-13-en-1-oic acid By the method of example 8, the

  Methyl ester of the acid (5 Z, 9 at, 13 E, 15 R, 16 R) -

  7,16-Difluoro-15-E (tetrahydro-2H-pyran-2-yl) oxy] 9-hydroxy-5-hydroxy-5-hydroxy-2-yl

  prsa 51-in 10u in methyl ester of the acid

  (9 at, 13 E, 15 R, 16 R) -7,16-difluoro-15-l (tetrahydro-2H-pyran)

  2-yl) oxyl-6,9-epoxy-5-iodo-prosta-13-en-1-ol.

  EXAMPLE 19 Methyl Ester of Acid (9A, 13E, 15R, 16R) -7,16-Difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-113-en By the method of Example 9, the trasform is

  Methyl ester of the acid (9x, 13E, 15R, 16R) -7,16-

  difluoro-15-1 (tetrahydro-2H-pyran-2-yl) oxyl-6,9-4-oxy 5-

  iodo-prosta-13-en-1-oi only in methyl ester of the acid

  <9a, 13E, 15R, 1-6R) -7,16-difluoro-15-hydroxy-6,9-epoxy-5-

  iodo-prosta 13-gn-1-oic Example 20 Methyl Ester of Acid

  (5 Z, 9ca, 13E, 15R, 16R) -7,16-Difluoro-6,9-4-poxy-15-hydroxy-

  With the method of Example 10, the procedure of Example 10

  methyl ester of the acid (9 x, 13 E, 15 R, 16 R) -7, 16-

  difluoro-15-hydroxy-6,9-px od-rsa 13 and in methyl ester of the acid (z 9, 3,5,6)

  7,16-difluoro-15-hydroxy-6,9-epoxy-prosta-5,13-dien-1-oique-

Example 21 Sodium salt of the acid

  (5 Z, 9 a L, 13 E, 15 R, 16 R) -7,16-Difluoro-6,9-epoxy-15-hydroxy

  prosta-5,13-dien-1-o'ic By the method of Example 1 i is transformed

  the methyl ester of the acid Z, 9 a L, 13 E, 15 R 16 R> -

  7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oic

  in the sodium salt of the acid <5 Z, 9 a, 13 E, 15 R, 16 R) -

  7-, 16-difluoro-6,9-epoxy-15-hydroxy-proposta-5,13-di-en-1-ol.

Example 22

Methyl ester of acid

  (4E, 9t, 13E, 15R, 16R) -7,116-Difluoro 6,9-epoxy-15-hydroxy-

  prosta-4,13-dien-1-oi that By the method of Example 10,

  the methyl ester of the acid (9 t, 13 E, 15 R, 16 R) -

  7,16-Difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-

  that is changed to the methyl ester of the acid (4 E, 9 ca, 13 E, 15 R, 16 R) -

  7.6 Example 23 By the method of Example 11,

  the methyl ester of the acid (4E, 9a, 13E, 15R, 16R) -

  7.1 16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oic is converted into the sodium salt of the acid

  (4E, 9a, 13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-1

prosta-4,13-dien-1-oi that.

Example 2> 4

  A tablet containing: Tablet Sodium salt of acid <5 Z, 9 a, 13 E,

  R, 16 R) -7,16-difluoro-6,9-epox Y-15-

  hydroxy-prosta-5,13-dien-1-olc 25 mg dicalcium phosphate dihydrate, unmilled 175 mg starch 2> 4 mg maesium stearate 1 mg Total weight: 225 mg The active ingredient is mixed with The corn starch is passed through a sieve / H 00 in the Fitzmill model "J" mill with the hammers forward. This premix is then mixed with dicalcium phosphate and half of the magnesium stearate is made. pass through a 4 / 1Z sieve into a Fitsmill model "J" mill with the knives forward, and knock down. The resulting products are passed through an H / 2 A plate into a Fitzmill Model "D" mill at low speed. with the knives in front and the rest of the magnesium stearate is added.

mix and compress.

Example 25

  One formulates a tablet in the same way - as in the example

  except that the methyl ester of the acid (4 E, 9 a, 13 E, 15 R, 16 R) -7,16-difluoro-

  6,9-epoxy-1,5-hydroxy-prosta-4.1 13-dien-1-oic

is the active ingredient.

Example 26

  A capsule containing the following ingredients is prepared: Per tablet Sodium salt of the acid

  (5 Z, 9 a, 13 E, 15 R, 16 R) -7,16-difluoro-6,9-

  epoxy-15-hydroxy-prosta-5,13-dien-1-oic mg Dicalcium phosphate dihydrate, unground 235 mg starch 70 mg FD & C Yellow / 5 Aluminum Lake 25% 2 mg Durkee Duratex * 25 mg Stearate calcium 3 mq 535 mg

  * Hydrogenated cotton oil (fully saturated).

  All of the above ingredients are mixed until thorough mixing is done in a suitably sized container. The powder is poured into two-piece hard gelatin capsules, A / 2. weight of 350 mg once the capsules

  filled using an encapsulator.

Example 27

  A capsule is prepared by the method of Example 24 except that the methyl ester of the acid

  (4E, 9a, 13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-

hydroxy-prosta-4,13-dien-1-olque

is the active ingredient.

Example 28

  3.3 to S, 4,5,6,6 to 5-hexahydro-3-fluoro-4 R-1,4-dimethyl-3 R-

  (2-Tetrahydropyranyloxy) -1-trans -octenyl-5-R-methyl-2H-

  cyclopentalblfuran-2-one To a solution of diisopropylamine in 9 ml of THF (tetrahydrofuran) cooled to 0-5 ° C., 1.32 ml of a 2.2M solution of n-butyllithium in hexane is added dropwise. The mixture is stirred for 5 minutes and cooled to -400 ° C. with a bath of dry ice and acetone. A solution of 1 g of water is added dropwise for 1 minute.

3,3 to R, 4,5,6, -

  6-S-hexahydro-4 R-1,4-dimethyl-3 R- (2-tetrahydropyranyloxy) -

  1-trans-octenyl-5-R-methyl-2H-cyclopentalblfuran-2-one in 6 ml of THF (tetrahydrofuran) and stirred at -451 ° C.

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  for 5 minutes Trimethylchlorosilane is then added

  (4.26 ml) and the mixture was stirred at -40 ° C for 5 minutes.

  The mixture is then allowed to warm to 00 ° C. and the solvent is removed under high vacuum. Diethyl ether (5 ml) is added to the residue and the cold mixture is filtered through a sintered glass funnel. The solvent is then removed under a vacuum. The solution is dissolved in ml of CH 2 Cl 2 and the solution at 00 ° C. is then added 530 mg of potassium bicarbonate followed by 429 mg of xenon difluoride. When the evolution of gas ceases, the mixture is stirred. The mixture is then stirred for a further 15 minutes with 50 ml of CH 2 Cl 2. The solution is then washed with 50 ml of H 2 O + 2 × 50 ml of brine. The aqueous phase is separated off and washed again with 50 ml. of CH 2 C 12 The aqueous strains are combined, dried (MgSO 4) and the solvents removed under pressure

  reduced to give 0.95 g of crude product. The chromatogra-

  on 50 g of silica gel gives

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  300 mg of 3,3 to S, 4,5,6,6 to 3-hexahydro-3-fluoro-4 R-114.4-

  dimethyl-3 R- (2-tetrahydrooyranyloxy) -1-trans-octylen-6-yl;

  Example 29 3, 3 to S, 4,5,6, 6 to SHexahydro 3-fluoro-4 R 4, 4-dimethyl-3 R (2-tetrahydropyranyloxy) -1 -transoctenyl J 2-R-methyl-2-cyclopentyl-furan-2-ol By the method of Example 6, the 3,3a, 4,5,6, 6a-S hexa was converted to

  hydro-3-fluoro-4 R-1,4-dimethyl-3 R- (2-tetrahydropyranyloxy) -

  1-trans-octenyl-5-R-methyl-2H-cyclo pentalb Jfuran-2 one

  at 3.3 to S, 4,5,6,6 to 5-hexahydro-3-fluoro-4 R-

  4,4-dimethyl-3 R- (2-t L <trahydropyra-nyloxy) -1-trans-octyl

  R-methyl 2H cyclopentalb I Ifuran 2-ol.

Example 30

Methyl ester of the acid

  11 R, 16,16-Trimethyl 7-fluoro-R- (2-tetrahydropyranyloxy) -

  S-hydroxyprosta-cis-5-trans-13-dieenoic acid By the method of Example 7, the

3., 3 to S, 4,5,6, 6 to S-hexa-

  hydro-3-fluoro 4 R-1,4-dimethyl-3-r- (2-tetrahydropyranyloxy) -

  1-trans-octen-5-methyl-2-methyl-cyclopentyl-3-furan-2-ol in methyl-

  ester of iron R 1,6 tih 17 fur-5-2 tta

  hydropyranyloxy) -9-hydroxyprosta-cis-5-trans-13-dienoic acid.

Example 31 Methyl ester of the acid

  (9S, 1R, 13E, 15R) -11,16,1 16-Trimethyl-15- (2-tetramydro)

  pyranyloxy) -6,9-poxy-7-fluoro-5-iodo-prosta-13-en-1-oic acid By the method of Example 8, the methyl ester of the acid R, tith

  luzocr -15- (Z-t-Erahydropyranyloxy) -9 S-hydroxyprosta-cis

  pyraniyloxy) -6,9-epoxy-7-fluoro-5-iodo-prostan-113-en-1-oi L methyl ester

Example 32

Methyl ester of acid

  (9S, 11R, 13E, 15R) -11,6,16-Trimethyl-15-hydroxy-6,9-epoxy-7-

  Fluoro-5-iodo prosta 13-een-1-oic By the method of Example 9, the methyl ester of the acid

(9S, 11R, 13E, 15R) -

  7-Fluoro-5-iodo-prosta-1-en-1-enol is converted to hydroxy-6,9-epoxy-7-fluoro-5-iodo-prostatic acid methyl ester 13-n-1. oic

Example 33

Methyl ester of acid

  epoxy-7-fluoro-prosta-5,413-dien-1-ol.

  and methyl ester of the acid By the method of Example 10, the methyl ester of acic

(9S, 11R, 13E, ISR) -

  11, 16, 16-methyl-1954-ydoxy-6,9-opoxy-7-chloro-5-prostano-11-enanoic

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  > 44 is converted to a mixture which is separated by the method of Example 10 into epoxy-7-fluoro-prosta-5,13-dien-1-oic acid methyl ester Calc. For HFO 7 21 H, 7 4.63 Found 24 39 4 C 70 1 H 9 7

C 70.00; H 9> 44; F 4.49

  IR 3615, 1733, 1694 cm; -ultraviolet X max 213 nm (E

12000)

  and methyl ester of (4 E, 9 S, 11 R, 15 R) 4,116,16 trimethyl-hydroxyl-6,9-epoxy-7-fluoro-4-adiothioic acid Calc C 70,21; H, 9.57; F, 4.63 Found C 70.19; H, 9.52; F 4.85 -1 IR 3615, 1735, 1670 cm

Example 3> 4

  Sodium salt of epoxy-7-fluoro-prosta-5,1 acid In the procedure of Example 11, the methyl ester of the acid

(5Z, 9S, 11R, 13E, 15R) -

  11,16,1 16-trimethyl-6,9-hydroxy-7-poxy-fluoro-prosta-

  , 13-dien-1-cy which is converted into salt of sodum of the acid

  IIR, 13E, 15R) -1,16,16-trimeethy 115-hydroxy-6,9-poxy-7-

fluoro-prosta 13-dien-1-6-diol

Example 35

  3.3 to S, 4,5,6,6 to 5-hexahydro-3-fluoro 4 AR-3 S- (2-tetrahydro-);

  2 H-Cyclopentylfluan-2-one By the method of Example 28, the

3, 3 to R, 4,5,6, Ga S-hexa

  hydro-4 R-C 3 S- (2-t) trahydropyranyloxylyl trans-ct JSR-

  (2-tetrahydropyranyloxy) -2H-cyclopentalb) furan-2-one is converted into

  3, 3a S, 4,5,6, Ga S-hexahydro-3-fluoro-4 R-1

  (2-teetrahydropyranyloxy) -1-trans-octenyl 1-5R- (2-tetrahydroxy)

  hydropyranyloxy) -2H cyclopentalb Jfuran-2-one.

  3, 3 to S, 4,5,6,6-S-Hexahydro-3-fluoro-4 R-13 S - (2-tetricyclo)

2 H-cyclopentalblfuran-2-one-

  By the method of Example 6, the 3, 3a S, 4,5,6, Ga S-hexa

  hydro-3-fluoro-4 R-13 S - (2-tetrahydropyranyloxy) -1-trans-

  oct 6 nyl J-5 R- (2-tetrahydropyranyloxy) -2H-cyclopentalblfuran

  2-one is converted to 3.3 to S, 4,5,6,6 to 5-hexahydro-3-fluoro-4R

  1,3-tetrahydropyranyloxy) -1-trans-octylyl-5-R- (2-

  tetrahydropyranyloxy) -2H-CY Clopefltalb Pfuran-2 ol.

Example 37

Methyl ester of acid

  11 R-, 15S-Di- (2-tetrahydropyranyloxy) -7-fluoro-9-hydroxy-dihydroxy-.

prosta-cis-5-trans-13-diénoque-

By the method of Example 7, the

3, 3 to S, 4,5,6, 6 to S-hexa

  hydro-3-fluoro-4R-13S- (2-tetrahydropyranyloxy) -1-tranls;

  octenyll-5 R- (2-tetrahydropyranyloxy) -2H-cycl-opentaifluran

  2-01 is converted to the methyl ester of the acid

  R, 15 S-di- (2-tetrahydropyranyloxy) -

  7-fluoro-9 S-hydroxy-prosta-cis-5-trans-13-dienoil

Example 38

Methyl ester of acid

  (9S, 11R, 13E, 15S) -11,15 Di- (2-tetrahydropyranyloxy) -6.9-

  Epoxy-7-fluoro-5-iodo-prosta-13-en-1-o) By the method of Example 8, the methyl ester of the acid hydropyranyloxy) -7 fur-Shdoyrsacs 5 13-dignoic cluster is converted to 13 E, 15 S) -11,15-di- (2-ttrahydropyranyl oxy) -6,9-epoxy-7 methyl ester

Example 39

Methyl ester of acid

  <9S, 1R, 13E, 15S) - 111g 15-Dihydroxy-6,9-eepoxy-7-fluoro-5-

  iodo-prosta-134 en-1-Oic By the method of Example 9, the methyl ester of

the acid (9S, 11I R, * 13E, 1155) -

  11,15-di- (2-tetrahydropyranyl) oxy) -65,9-poxy-7-fluoro-5-

iodo-prosta-13-efl l Oque

Z'515644

  is converted to the methyl ester of the acid

  <9S, 11R, 13E, 15S) -11,15-dihydroxy-6,9-4-poxy-7-fluoro.

iodo-prosta-1 3-4 n-1-o'1 that

Example 140

Methyl ester of acid

  (5 Z, 9S, 11R, 13E, 15S) -11,15-Dihydroxy-6,9-epoxy-7-fluoro

prosta-5,13-dien-l-o'i that

  and methyl ester of the acid <4 E ,, 95,11 R, -

  R) -11,15-Dihydroxy-6,9-epoxy-7-fluoro-4,13-dien-1-O-By the method of Example 10, the methyl ester of

the acid (9S, 11R, 13E, 55s) -

  11,15-dihydroxy-6,9-poxy-7-fluoro-5-iodo-prosta-13-enol is converted to a mixture which is separated by the method of Example 10 to produce the ester methyl acid

  (5Z, 9S, 11R, 13E, 15S) -1,1, 15-dihydroxy-6,9-

  epoxy-7-fluoro-prosta-5,13-dieen-1-O and the methyl ester of the acid

  (4.9 S, 11.15 S) -11,1-dihydroxy-6,9-epoxy-7-fluoro-.

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Example 411

Sodium salt of acid

  (5 Z, 9S, 11R, 13E, 15S) -11,15-Dihydroxy-6,9-epoxy-7-fluoro

  prosta-5,13-dien-1-olc By the method of Example 11, the methyl ester of

  the acid <5Z, 9S, 11R, 13E, 15s) -

  dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-ol is converted to the sodium salt of the acid

<SZ, 9 S, 11 R, 13 E, 1 SS> -11,15-

  6-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-11-oi

Claims (6)

  1 / Compound of general formula: F HO O CH-CH = CH-CH 2 -CH 2 -CH 2 -C-OR * z z R 21 CH-C-C-CH 2 -CH 2 -CH 2 -CH 3 1 4 12   OR R wherein: R 2 R 2 is hydrogen, methyl or fluoro; OR 4 forms a removable ether protecting group; R 6 is lower alkyl; R1 is hydrogen, methyl or -OR4, and   R 21 is hydrogen, fluoro, trifluoro-   methyl or methyl, with the proviso that when R 21 is trifluoromethyl,   R 2 is hydrogen or methyl.   2 / Compound of general formula as defined in claim 1, wherein R 1 is constituted   by the group -OR defined in claim 1.   3 / The methyl ester of the acid (5 Z, 7 R, 9a, 11a, 13E, 15R) -7-fluoro-11,15-di (tetrahydro-2H-pyran-2-yl) oxy l-16,16-dimethyl-9-hydroxyprosta-5,13-dien-1-oic acid according to claim 1.   4 / Compound of general formula as defined in claim 1, wherein R1 is an atom hydrogen.   / The methyl ester of the acid (5 Z, 9 a, 13 E, 16 R) -   7,16-Difluoro-15 (tetrahydro-2H-pyran-2-yl) oxy 7-9-   hydroxy-prosta-5,13-dien-1-oic according to claim 1.   6 / Process for the preparation of a compound according to one   Claims 1 to 5, characterized in that one   reacting a compound of the general formula OH _ F X 1 OR 4 2 2 2 R 21 CH = CH-CH, -C-CH 2 -CH 2 CH 2 -CH 3   with a phosphonium salt of formula B R O have OR 6 R P -CH (CH H-2 CH 2 2 y (R 2 4 6 he 21   in which R 2, OR, R, R and R have the significances   given previously and Ra, Rb, Rc represent aryl or di (lower alkyl) amino and Y is a halogen.   7 / Application of the compounds according to one of the claims   cations 1 to 5 to the manufacture of fluoroprostacyclines useful as medicines. gold