IE52389B1 - Intermediates for the preparation of fluoro-phostacyclins - Google Patents

Description

The present application Is divided out of out Patent Specification No. 547/82 filed on 10 Match 1982.

The present invention relates to compounds of the general formula wherein: κ is lower alkyl; 41 R is hydrogen, methyl or OS ; R xs methyl, hydrogen or fluoro; R is fluoro, hydrogen, trifluoromethyl or methyl; X is halogen; and 41 OR is hydroxy or forms a hydrolyzable ether protecting group, with the proviso that when R is trifluoromethyl, R is hydrogen or methyl and to their optical antipodes and racemates.

These compounds are useful intermediates for the preparation of novel fluoro-prostacyclins of the general formula 1. wherein one of the double bonds indicated by broken lines is present in 4,5 or 5,6 position; R is hydrogen or lower 1 2 alkyl; R is methyl, hydrogen, or hydroxy; R is hydrogen, 21 methyl or fluoro; and R is hydrogen, fluoro, trifluoromethyi or methyl; with the proviso that when R 2 is trifluoromethyi, R is hydrogen or methyl.

Our Patent Specification No. 547/82 relates to these novel fluoro-prostacyclins and their pharmaceutically acceptable salts, optical antipodes or racemates.

Preferred compounds of the formula 1 are those of formula 1-A.

O -CH-CH /C ;h-ch2-ch2-ch2-c-or R?1 Ϊ-Α CHsCH-CH-C-CH2-CH£-CH2-CH3 oh r? 21 wherein R, R . R and R are as above.

In another aspect, the present parent application is - 4 concerned with compounds of the formula 1-B.

As used throughout this application, the term lower alkyl refers to both straight chain and branched chain alkyl groups having from l to 7 carbon atoms such as methyl and ethyl. As also used herein, the term lower alkanoic acids refers to alkanoic acids 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, refers to fluorine, chlorine, bromine or iodine. Alkali metal refers to all alkali metals, such as lithium, sodium and potassium.

All compounds according to the present invention having one or more asymmetric carbon atoms can be produced as racemic mixtures. These racemic mixtures which are obtained can be resolved by methods well known in the art whereupon subsequent products may be obtained as the corresponding optically pure enantiomers.

In the pictorial representation of the compounds given throughout this application, a thickened taper line (Y ) indicates a substituent which is in the beta-orientation (above the plane of the molecule), a dotted line (iimi ) indicates a substituent which is in the alpha-orientation - 5 (below the plane of the molecule) and a wavy line (-wv) indicates a substituent which is in either the alpha- oc beta-ocientation oc aixtuces of these isomecs. It is to be undecstood that the pictocial representations of the compounds given thcoughout the specification ace set focth foe convenience and ace to be constcued as inclusive of othec forms including enantiomers and racemates and ace not to be constcued as limited to the pacticulac form shown.

As also used hecein, the teem acyl signifies mono-nucleac aromatic hydrocarbon groups, which can be unsubstituted oc substituted in one oc moce positions with'' a lower alkylenedioxy, nitco, halo, a lower alkyl oc a lowec alkoxy substituent, such as phenyl and tolyl and polynuclear acyl groups such as naphthyl, anthcyl, phenanthryl and azulyl. which can be unsubstituted oc substituted with one oc moce of the aforementioned groups. The pceferced acyl groups ace substituted and unsubstituted mono-nuclear acyl groups, particularly phenyl. The term ether protecting group removable by acid catalyzed cleavage designates any ether which, upon acid catalyzed cleavage yields the hydroxy group. A suitable ether protecting group is, for example, the tetrahydropyranyl ether, oc 4-methyl-5,6-dihydro-2H-pyranyl ether. Others are arylmethyl ethers such as benzyl, benzylhydryl, or trityl ethers or alpha-lower alkoxy lowec alkyl ether, for example, methoxymethyl or allylic ethers, or tci(lowec 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 tetrahydropyranyl and the tri(lowec 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 ace the mineral acids such as sulphuric 2 389 acid, and hydrohalic acids. Among the preferred organic acids are lower alkanoic acids such as acetic acid and para-toluene sulphonic acid. The acid catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent medium. Where an organic acid is utilized, the organic acid can be the 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 not critical and this 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 the beta configuration. Among the 7-beta fluoro compounds, the following are preferred: ch-ch,-ch,-ch2-c-or F * ΟI-Ai OH CH, f CHCH-CH -C—CHj-CHj-Clij-CHj oh CH, CH-CHj-CBj-CHj-C-OR OH I-Aii CH=CH-CH-CH -CH2-CH,-CH2-CH3 UH ^M^-ch^-or Γ 1 f*3 X^*ch=ch-^iw3—ch2-ch2-ch2-ch3 r-Ain CH, OH CH, JCH-CH2-CH2-CH2-C-OR S4F H=CH-£ Ch, £H -ch-ch2-ch2-ch2-ch3 OH F I-Aiiii When R is lower alkyl in the compound of formulae ϊ-Ai. 1-Aii. I-Aiii and 1-Aiiii, R is preferably methyl or ethyl.

The compounds of formula I ace prepared from a compound of formula R21' II i1 2-ch2-ch2-ch3 Sh r2 2 21 wherein R , R and R are as above, or optical antipodes or racemates thereof, via the intermediates IV to XII: IV ,21 R-11 • H? CH=CH-CH -C -CH„-CH.-CH„-CH, — i 4 Z Z 3 — 4 ' O or’r-* CH=CH-CH -C -CH2-CH2-CH2-CH3 OR4R2 Ρ ,21 VI °<3 CH=CH-£H -C. -CH2-CH2-CH2-CH3 = 4 I2 OR R vn t21 *4 CH»CH-CH-C -Cf£-CH2-CH2-CH3 _ * 2 oh sr OH VUI HO ^HIUCH -ch=ch-ch.-ch,-ch,-cooh ( & Ά CH=CH-CH -c—CH,-CH.-CH,-CH, I I 2 2 2 2 4 S OR411 IX HQ^ ^CH -CH=CH-CH2-CH2-CH2-C00R ,21 CH=CH-CH -c— CH-CH -CH„-CH„ 11 4 12 2 2 2 3 OR R Η\/ °Η“ ?...........L·' CH -ch2-ch2-ch2-c-or' F CL R21 XH CH=CH-£H -C -CH2.-CH2-CH2-CH3 OR R2 - CHXL· CH-CH2-CH2-CH2-C-Off F ,6 I?1 xnr fCH=CH£H-C -CH2-CH2-CH2-CH3 2 OH I2 XVI S3389 - 12 1 2 21 11 wherein R. R, R and R are as above, R is 4 hydrogen, methyl or OR ; -OR forms an ether protecting group removable by an acid catalyzed cleavage; R6 is lower alkyl; X is halogen; and R5 is tri(lower alkylJsilyl.

The compound of formula II is converted to the compound of formula IV by conventional etherification in order to protect any free hydroxy groups in the compound of formula 11. Where R1 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 preferred ethers for use in this reaction are tetrahydropyranyl and dimethyl-t-butyl silyl ether. In carrying out this reaction, any conventional method of etherifying the compound of formula 11 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 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 compound of formula V by first enolizing the compound of 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. 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 base, temperatures of -70 to -30° are generally preferred. Generally, this reaction is carried out in an inert organic solvent. Any conventional inert organic solvent which is a liquid at the aforementioned temperatures can 32389 - 13 be utilized. Among the preferred solvents is tetrahydrofuran. The enolate of the compound of formula IV in the form of its alkali metal salt is converted to the compound of formula V by treating the compound of formula V with a trialkyl halosilane. preferably trimethylchlorosilane. Generally, this reaction is carried out at the same temperatures and in the same solvent utilized to form the enolate.

The compound of formula V is converted to the compound 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 and fluorine gas. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized in carrying out this reaction. Among the preferred solvents are halogenated hydrocarbons such as methylene chloride and carbon tetrachloride. In carrying out this reaction, temperature 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 -1O°C to +1O-C.

In converting the compound of formula V to the compound of formula VI, the compound of formula Vl is produced as a mixture of the following compounds: - 14 Λ-· ,21 VI-A - “CH=CH~CH -C -CH.-CH,-CH„-CH, 11 “ I 4 λ 4 J OR4 R2 R II ,21 VI-B ^CH=CH-gH -C -CH2-CH2-CS2-CH3 OR4R2 wherein R11. R2 and R21 are as above.

The compounds of formulae VI-A and Vl-B can be separated by conventional methods such as chromatography.

On the other 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, separated at some later state in the reaction scheme to produce the compound of formula I having the desired fluoro orientation at the 7-position. If the compound of formula VI is separated into the compounds of-formulae Vi-A and VI-B. the same configuration of the fluorine atom is carried on throughout the rest of the reaction. There15 fore, if the compounds of formula I wherein the fluorine atom is at the 7-beta position, are desired, the compound of formula Vl-A is utilized in the rest of the reaction scheme producing compounds of the formulae VII through XVI wherein the fluorine atom set forth in these formulae is in the beta position. If the compounds formula 1 are desired wherein the fluorine is in the 7-alpha position. 32389 then the compound of formula VI-B is utilized in the reaction scheme to produce the compounds of formulae VII through 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 utilized without separating it into the compounds of formulae Vl-A and VI-B. In this manner, the compounds of formula 1 wherein the fluorine is in both of the alpha and beta positions is produced via intermediates of the formulae VII through XVI having the fluoro group in the same position as shown.

In converting the compound of formula 11 to the compound of formula VI, it is generally preferred to utilize the tri(lower alkyl)silyl ethers as the hydroxy protecting group. In the conversion of the compounds of formula VI to the compounds of formula I it is generally preferred to protect one or more of the hydroxy groups with a tetrahydropyranyl ether. On the othec hand, the silyl ethers or any othec conventional ethers can be utilized in the rest of this process. However, it is preferred that the silyl ethers of formula Vl are hydrolyzed to produce the compound of formula VII which is then reetherified to produce the compound of formula Vl wherein the ether group is tetrahydropyranyl. Any conventional method of hydrolyzing ethers can be utilized to carry out the conversion of the compounds of formula Vl to the compounds of formula VII and any conventional method of etherification can be utilized to carry out the reconversion of the compounds of formula Vll to the compounds of formula VI. With tetrahydropyranyl as the protecting group in the compound of formula Vl, there is no need to hydrolyze the compound of formula VI to the compound of formula VII since the compound of formula VIII can be produced directly from the compound of formula VI.

The compound of formula Vll la converted to the compound of formula VIII by treating the compound of formula Vll 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 aluminium hydrides such as alkali metal aluminium hydride, and the borohydrides such as alkali metal borohydrides, with diisobutyl aluminium hydride being particularly preferred. Also, this reaction can be carried out utilizing di(branched chain lower alkyl)boranee such as bis(3-methyl-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 -8O°C 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 solvents are dimethoxyethylene glycol, and the ethers such at tetrahydrofuran, diethyl ether and dioxane.

The compound of formula IX is obtained from the compound of formula VIII by reacting the compound of formula Vlll with phosphonium salts of the formula ί f CH2“ O XX-A 52388 - 17 wherein each of Ra, Rb, R° is either aryl or di(lower alkyl) amino, and Y is halogen. via a conventional Wittig type reaction. Any of the conventional conditions in Wittig reactions can be utilized in carrying out this reaction.

The compound of formula IX can be converted to a compound of the formula X by esterification with diazomethane or a reactive derivative of a lower alkanol such as a lower alkyl halide. Any conventional conditions utilizing 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 Xl by treating the compound of formula X with a halogenating agent. Among the preferred halogenating agents are included N-haloeuccinimides, particularly N-iodosuccinimide. Generally, this reaction is carried out in the presence of a polar solvent such as acetonitrile and halogenated 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 35*c can be utilized. Generally, it is preferred to carry out this reaction at room temperature.

The compound of formula XI is converted to the compound 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 - 18 carrying out this reaction, any conventional dehydrohalogenating agent can be utilized. Among the preferred dehydrohalogenating agents are the diazabicycloalkanes or alkenes such as l,8-diazabicyclo[5.4.0]undec-7-ene and 1.4-diazabicyclo[2.2.2]octane. Furthermore, any other conventional organic base utilized for dehydrohalogenation can be utilized in carrying out this reaction. This reaction produces the compounds of formula Kill and the compounds of formula XIV in admixture. The compounds of formula Xlll can be separated from the compounds of formula XIV by any conventional procedure such as chromatography.

The compound of formula Xlll is converted to the compound of formula XV and the compound of formula XIV is 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 formula Xlll or the compound of formula XIV with a alkali metal hydrozide. Among the preferred alkali metal hydrozides for use in this reaction are sodium and potassium hydroxides.

The present invention relates to compounds of the formulae XI and XII given above.

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

The Examples show the preparation of the compounds of the present invention and their use in the preparation of - 19 the novel fluoro prostacyclin· of our copending application.

Example 1 [3aR-[3aa,4a (IE.3R«).5fl.6aa]]-Hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(l,l-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one. 502.2 mg (1.69 mmol) of [3aR-[3aa.4a(lE,3R*).5fi.6aa]]hexahydro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-l-octenyl)-2H-cyclopenta[b]furan-2-one, was dissolved in 15 ml of dimethylformamide (reagent grade, dried over 3% molecular sieves) under a positive argon pressure. 1.045 g (6.93 mmol » 4.09 eq.) of t-butyldimethylchloroeilane (dist. before use) and 587.6 mg (8.63 mmol - 5.09 eq.) of imidazole (reagent grade) were added. The resulting mixture was stirred at room temperature for 18 h, poured into 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 NaHCOg/HgO/brine - 1:1:2 followed by washing with 60 ml brine. The extracts were combined, dried over Mgso* 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 ether (first lit) followed by 20% by volume ether/80% by volume petroleum ether. 857.1 mg (1.63 mmol. 96.4c) of (3aS-[3aa,4a(lE,3R*),5fl,6aa]]-hexahydro-5-[[(1.i-dimethylethyl)diraethylsilyl]oxy)-4-[[[3-(1,1 dimethylethyl)dimethylsilyl]oxy]-4,4—dimethyl-l-octenyl]-2H-cyclopenta[bjfuran-2-one as a white amorphous solid was obtained; m.p. 67-68°. - 20 Example 2 [3aR-[3aa,4a(lE,3R*).5fl,6aa]]-4.5,6,6a-Tetrahydro—5-[[l ,l-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,l-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-l-octenyl]-25 -(trimethylsilyl)oxy-3aH-cyclopenta[b]fUEan.

I 570 μ1 (4.07 mmol) of diisopropylamine (dist. from CaH2) was dissolved in 15 ml of tetrahydrofuran (freshly dist. from LAH). The mixture was cooled to +3°C under a positive argon pressure. 2.5 ml (3.75 mmol) of 1.5 N n-butyllithium in hexane was added dropwise at +3aC. After stirring at +3aC for 5 min, the mixture was cooled to -40eC with a dry ice/acetone bath. 1.757 g (3.35 mmol) of [3aR-[3aa,4a(lE,3*R),5B,6aa]]-hexahydro-5-[[(1.1-dimethylethyl) dimethylsilyl] oxy] -4-[[[ 3-(1, 1-dimethylethyl )15 dimethylsilyl]oxy]-4.4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one dissolved in 6 ml THF was added dropwise to the lithium diisopropylamide solution at -40eC. After stirring at -40°C for an additional 5 min, 570 μΐ (4.49 mmol) of trimethylchlorosilane (dist.) was added rapidly. Two min. after the addition, the cooling bath was removed and the mixture was allowed to warm to +15°C 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 15 min. 10 ml of ether (freshly filtered through aluminium oxide, activity I) was added under argon and the mixture was filtered through a sintered glass funnel. The white residue was washed three times with 3 ml of ether. The slightly yellow filtrate was concentrated under vacuum and the oily residue was dried at high vacuum (room temperature) for 1 h producing [3aR-[3aa,4a-(IE,3*R),5β,6aa]]-4,5,6,6a-tetrahydro-5-[[(l«l-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,l-dimethylethyl )dimethylsilyl]oxy]-4.4-dimethyl-l-octenyl]-2-(trimethylsilyl)oxy-3aH-cyclopenta[b)furan. - 21 Example 3 [3S-[3a.3aa.4a(lB.3«K).5fl,6aa]]-Hexahydro-3-fluoro-5-([(l,l-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl)oxy]-4.4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one The compound [3aR-[3aa.4a(lE,3*K),5fl.6a«t])-4,5,6,6a-tetrahydE0-5-r[l.l-dimethylethyl)dimethylailyl)oxy]-4-[[[3-(l,l-dimethylethyl)dimethyleilyl]oxy]-4.4-dimethyl-l-octenyl]-2-(trimethylsilyl)oxy-3aH-cyclopenta(b]furan was dissolved in 15 ml of methylene chloride (freshly filtered through aluminium oxide, activity I) under argon. The mixture was cooled to +2’C with an ice/water bath. 680 mg (6.8 mmol) of potassium bicarbonate (dried at high vacuum at 100° over p2°5 for 3 h) followed by 632.9 mg (3.73 mmol) of xenon difluoride were added under stirring. An immediate reaction ensued as judged by the vigorous gas evolution in the first 30 sec. after the addition of XeF2· The mixture was stirred at +2®C for 20 min, poured into 150 ml of ice cold water and extracted three times with 150 ml of methylene chloride. The extracts were washed twice with 150 ml of brine, combined, dried over MgSO^ 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 acetate/95* by volume petroleum ether (1 It) followed by 10* ethyl acetate/ petroleum ether were used as eluting solvents. The following products were obtained in order of elution: 1.06 g (1.95 mmol) 58* of [3S-[3a,3aa,4a(lE,3«R),5S,6aa]]-hexahydro-3-fluoro-5-[[(1.1-dimethylethyl)dimethyl- 22 silylJoxy]-4-[[[3-(1,l-dimethylethyl)dimethylsilyl]-oxy]-4.4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one; white needles formed on standing, m.p. 49-51”; 165.2 mg (0.315 mmol) 9.4* of [3aR-[3aa,4a(lE,3«R).5fl,6aa]]-hexahydro-5-[[(l,l-dimethylethyl)dimethylsilyl]oxy]-4-[[[3(1,1-dimethylethyljdimethylsilyl]oxy]-4.4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one. starting material; and 98.9 mg (0.182 mmol) 5.4* of 3R-[3B.3aa.4a(lE.3«R),5fl.6aa]-hexahydro-3-fluoro-5-[[(l,l-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-{l,l-dimethylethyl)dimethylsilyl]-oxy]-4,4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one; amorphous white solid: m.p. 83-85°.

Example 4 [3S-[3a,3aa,4a(lE,3*R).5B,6aa]]-Hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-l-octenyl)-2H-cyclopenta[b]furan-2-one. 1.597 g (2.94 mmol) of the fluoro lactone [3S-[*a,3aa.4a(lE.3«R).5B 6aa]-hexahydro-3-fluoro-5-[[(l.l-dimethylethyl)dimethylsilyl]loxy]-4-[[[3-(1,1-dimethylethyljdimethylsilyl]oxy]-4,4-dimethyl-l-octenyl]-2H-cyclopenta[b]furan-2-one was dissolved in 60 ml of acetic acid (reagent grade) and the mixture was warmed to 55°c under a positive argon pressure. 6 ml of water was added with stirring at 55”C. After 7 h. an additional 4 ml of water was added and stirring at 55”C was continued for 64 h (71 h total). After cooling to room temperature, the solvent was removed under vacuum (ca. 0.2 Tore) at 25-30°C. The oily residue was dried at high vacuum for 2 h at room temperature, followed by chromatography on 200 g of silica gel (230-400 mesh) using solvent mixtures rangeing from ethyl acetate/petroleum ether 1:1 parts by volume to pure ethyl acetate for elution. - 23 351.2 mg of partially hydrolyzed material containing large amounts of impurities and 571.5 mg (1.82 mmol, 62%) of [3S-[3a,3aa,4a(lE.3«R).5«,6aa]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4.4-dimethyl-l-octenyl)-2H-cyclopenta[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 mmol) 4.3% of additional [3S-(3a.3aa.4a(lE.3*R),6B.6aa)]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-l-octenyl)-2H-cyclopenta[b]furan-2-one. Total yield of [3S-[3a.3aa,4a(lE.3«R).5fl,6aa)]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4.4-dimethyl-l-octenyl)-2H-cyclopenta[b]furan-2-one was 611.1 mg (1.94 mmol) 66%, oil, clear.

Example 5 [3S-[3a,3aa,4a(lE,3*R),5J3.6aa]]-Hexahydro-3-fluor0-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-(3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-l-octenyl]-2H-cyelopenta[b]furan-2-one 571.5 mg (1.83 mmol) of (3S-(3a,3aa.4a(lE,3«R),5fl,6aa]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4-4-dimethyl-l-octenyl)-2H-cyclopenta[b]furan-2-one was dissolved in 20 ml of methylene chloride (freshly filtered through aluminium oxide, activity 1) under a positive argon pressure. 2.0 ml (21,9 mmol) of dihydropyran (freshly diet, from sodium) was added under stirring followed by a crystal of p-toluenesulphonic acid monohydrate (9.7 mg; 0.05 mmol). The mixture was stirred at room temperature for 30 min, poured into 50 ml of sat. agueous sodium bicarbonate and extracted three times with 30 ml of methylene chloride. The extracts were washed twice with 50 ml of brine, combined, dried over MgSO4 and concentrated at reduced pressure. The crude product (1.14 g, oil) was chromatographed on a 100 g silica gel column with ether/petroleum ether (1:1) yielding 797 mg (1.65 mmol) 91% of [3S-[3a,3aa.425 - 32.46’ in CHClj, c - 0.8780.

Example 6 [3S-(3a,3aa.4a(lE,3*R),5fl,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-ol After dissolving 729.2 mg (1.51 mmol) of [3S-[3a,3aa.4a(lE,3«R).5B.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. -70°c with a dry ice/acetone bath. 1.25 ml (1.75 mmol) of a 1.4M solution of diisobutylaluminium hydride in hexane was added dropwise at -70’C. The mixture was stirred at -7O’C for 20 min. 3 ml of a saturated aqueous ammonium chloride solution was added dropwise at -70°C and the resulting mixture was transferred with 20 ml of water and 50 ml of ethyl acetate into a separatory funnel. Shaking caused a very thick suspension to form, which was filtered through Celite (Trade Mark). The residue was washed thoroughly with 100 ml of ethyl acetate. The filtrate 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 aqueous washings were reextracted once with 80 ml of - 25 ethyl acetate. The organic extracts were combined, dried over MgSO* and concentrated at reduced pressure. Flash chromatography on 200 g of silica gel (230-400 mesh) of the crude product (806 mg; oil) with ethyl acetate/petroleum ether (4:6) gave 661.6 mg (1.36 mmol) 90* of [3S-(3a,3aa,4a(lE,3*R),5fl,6aa]]-hexahydro-3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxyJ-4-(3-((tetrahydro-2H-pyran-2-yl)oxy]-4,4-d imethyl-l-octenyl]-2H-cyclopenta25 [b]furan-2-ol as an amorphous solid, m.p. 58-66oc; [o)D -12.83° in CHClj. C - 1.0290.

Example 7 (5Z,7R,9 1.54 g (3.47 mmol) of (4-carboxybutyl)triphenylphosphonium bromide (dried at high vacuum at lOO’C over P2O5 for 2 h) and 1..275 g (6.95 mmol) of sodium hexamethyldisiliazane (dist.) 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 dropwise a solution of 560.5 mg (1.16 mmol) of (3S-[3a,3aa,4 Most of the solvent was evaporated under high vacuum at or below room temperature. The residue was transferred with 100 ml of ether and 100 ml of water into a separatory 52388 - 26 funnel. The aqueous phase was acidified to pH 3 with 13 ml of IN HC1. After shaking and separation of the two phases, the aqueous phase was reextracted twice with 70 ml of ether. The organic extracts were washed twice with 70 ml of brine, combined and dried over MgSO^. 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 aluminium oxide, activity 1) and exterified at room temperature by the addition of 15 ml (3.75 mmol) of a =>.25N solution of diazomethane 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 1.0M solution of tetra-n-butyl15 ammonium 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, dried over MgSO^ and concentrated at reduced pressure. 1.24 g of a yellow oil was obtained. Chromatography on 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) gave 20.8 mg (3.7%) of [3S-(3a.3aa,4a(lE.3*R.5fl.6ao]]-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-ol (startihg material) and 496.3 mg (0.85 mmol) 73% of (5Z,7R,9a,llD = +2.74° in CHC13. c » 0.9116. - 27 Example 8 (78.9α,11α.13E.158)-16.16-Dimethyl-ll.15-di[(tetrahydro-2H-pyran-2-yl)-oxy]-6.9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic aeid methyl estet. 246.9 mg (0.424 mmol) Of (5Z.7R,9a,lla,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 was dissolved in 10 ml of acetonitrile (dried over 3A molecular sieves) under a positive argon pressure. 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 aluminium foil to protect the reaction mixture from light. The mixture was stirred at room temperature for 27 h, poured into 100 ml of a 10* weight by volume solution of sodium thiosulphate in water and extracted three times with 100 ml of methylene chloride. The organic extracts were washed twice with 100 ml of brine, combined, dried over MgSO* 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 pacts by volume) gave 186.8 mg (0.263 mmol) 6Z% Of (78.9a.Ila,13E,158)-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 (oil) as a mixture of diastereomers.

Example 9 (78,9α.11α,13E,15R)-16,16-Dimethyl-ll.15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-l3-en-l-oic acid methyl ester .6 mg (15 umol) of (7B.9a.lla.l3E.15R)-16,16-dimethyl-ll,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-6.952389 - 28 -epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester was dissolved in a mixture of 3 ml of tetrahydrofuran (freshly 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 40°C 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 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 (7J3,9a,lla,13E,15R)-16,16-dimethyl-ll,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester (oil) as a mixture of isomers.

Example 10 [3aR-[3aa.4a(IE,3R*.4R*)6aa]]-Hexahydro-4-[[[3-(l,l-dimethyl-ethyl)dimethylsilyl]oxy]-4-fluoro-l-octeny1]-2H-cyclopenta[b]furan-2-one By the procedure of Example 1 [3aR-[3aa.4a20 (lE.3R*,4R*)6aa]]-hexahydro-4-[4-fluoro-3-hydroxy-l-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-l-octenyl)-2H-cyclopenta[b]furan-2-one.

Example 11 [3aR-[3aa,4a(lE,3R*,4R*)6aa]]-Hexahydro-3-fluoro-4-[[[3-(1,1-dimethylethyl)dimethyIsilyl]oxy]-4-fluoro-l-octenyl]-2H-cyclopenta[b]furan-2-one By the procedure of Examples 2 and 3, [3aR-[3aa,30 4a(IE,3R*,4R*)6aa]]-hexahydro-4-[[[3-(1.1-d imethy1S2389 - 29 ethyl)dimethylsilyl3oxy3-4-fluoro-l-octenyl]-2H-cyclopenta[b]furan-2-one was converted to [3aH-[3aa,4a(1E.3R*,4R*)6aa3]-hexahydro-3-fluoro-4-[[[3-(l.l-dimethylethyl)dimethyleilyl] oxy3-4-fluoro-l-oetenyl]-2H-furan-2-one.

Example 12 j [3aR-[3aa,4a(lE,3R*,4R»)6aa33-Hexahydro-3-fluoro-4-(3-hydroxy-4~fluoro-l-octenyl]-2H-cyclopenta[b]furan-2-one By the procedure of Example 4 [3aR-[3aa.4a{IE,3R*,4R*)6aa] 3-hexahydro-3-fluoro-4-[[[3-(1,l-dimethylethyl)dimethyleilyl]oxy]-4-fluoro-l-octenyl]-2H-cyclopenta[b]furan-2-one was converted to [3aR-[3aa,4a(lE,3R«,4R*)6aa]]-hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-i-octenyl]-2H-cyclopenta[b]furan-2-one.

Example 13 [3aR-[3aa,4a(lE,3R’,.4R*)6aa]]-Hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-l-octenyl]-2H-cyclopenta[b]furan-2-one By the procedure of Example 5 [3aR-[3aa,4a(lE.3R*,4R*)6aa]]-hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-l-octenylJ-2H-eyclopenta[b]furan-2-one was converted to [3aR]3aa.4a(lE.3R*.4R*)6aa]]-hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-l-octenyl]-2H-cyclopenta[b]furan-2-one.

Example 14 3aR-[3aa.4a(lE,3R*,4R*)6aa3 J-Hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-l-octenyl]52389 - 30 -2H-cyclopenta[b]furan-2-ol By the procedure of Example 6 [3aR-[3aa.4a(lE,3R«,4R*)6aa]]-hexahydro-3-£luoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-l-octenyl]-2H-cyclopenta[b]5 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-l-octenyl]-2H-cyclopenta[b]furan-2-ol.

Example 15 (5Z.9a,13E.15R.16R)-7.16-Difluoro-l5-[(tetrahydro-2H10 -pyran-2-yl)oxy]-9-hydroxy-5,13-dien-l-oic acid methyl ester By the procedure of Example 7 [3aR-[3aa,4a(IE.3R*,4R*)6aa]]-hexahydro-3-fluoro-4-[ 3- [ {tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-l-octenyl]-2H-eyclopenta[b]15 furan-2-ol was converted to (5Z,9a,13E,15R,16R)-7.l6-difluoro-15-tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-prosta— -5,13-dien-l-oic acid methyl ester.

Example 16 (9α.13E,15R,16RJ-7.16-Difluoro-15-[(tetrahydro-2H20 -pyran-2-yl)oxy]-6.9-epoxy-5-iodo-prosta-13-en-l-oic acid methyl ester By the procedure of Example 8, (5Z.9a.13E.15R,16R)-7.16-difluoro-15-[(tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-prosta-5,13-dien-l-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-l-oic acid methyl ester. - 31 Example 17 (9α,13E,15R,16R)-7,16-Difluoro-15-hydroxy-6.9-epoxy-S-iodo-prosta-13-en-l-olc acid methyl ester By the procedure of Example 9, (9a.l3E,15R,16R)-7,16-difluoro-15-[(tetrahydro-2H-pyran-2-yl)oxy]-6.9-epoxy-5-iodo-prosta-l3-en-l-oic acid methyl ester was converted to (9a,l3E,15R,16R)-7,16-difluoro-15-hydroxy-6.9-epoxy-5-iodo-prosta-13-en-l-oie acid methyl ester.

Example 18 3,3as,4,5.6.6as-Hexahydro-3-fluoro-4R-[4.4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopentafbjfuran-2-one To a solution of diisopropylamine in 9 ml of THF (tetrahydrofuran) cooled to 0°-5°c, was added dropwise 1.32 ml of a 2.2M solution of n-butyllithium in hexane.

The mixture was stirred for 5 min and cooled to -40°C 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 ) -1-trans-octenyl ]-5R-methyl-2H-cyclopenta[b]furan-2-one in 6 ml of THF (tetrahydrofuran) was added dropwise over 1 minute and stirred at -45®C for 5 min. Trimethylchlorosilane (4.26 ml) was then added and the mixture etirred at -4O°C for 5 min. The mixture was then allowed to warm to O’C and the solvent removed under high vacuum. Diethyl 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 CH2C12. To the solution at O’C was then added 530 mg of potassium bicarbonate followed by 429 mg of xenon difluoride. After the gas evolution ceased, the mixture was etirred for an - 32 additional 15 min and diluted with 50 ml of CH2C12.

The eolution was then washed with 50 ml of H2O + 2 x 50 ml of brine, The aqueous phase was separated and back washed with 50 ml of CHjClj. The organic layers were combined, dried (Mgsop and the solvents removed under reduced pressure to give 0.95 g of crude product. Chromatography on 50 g of silica gel afforded 300 mg of 3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[4,4-dimethyl-3R-(2-tetrahydr opyranyloxy ) -l-trans-octenyl ]-5R-methyl-2H-cyclo10 penta[b]furan.

Example 19 3.3aS,4,5.6.6aS-Hexahydro-3-fluoro-4R[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-l-trans-octenyl]-5R-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-3R-(2-tetrahydropyranyloxy)-l-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-one was converted to 3,3as,4,5.6.6aS-hexahydro-3-fluoro-4R-[4.4-dimethyl-3R-(2-tetrahydropyranyloxy)-l-trans20 -octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-ol.

Example 20 11R,16,16-trimethyl-7-fluoro-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoic acid methyl ester By the procedure of Example 7,3.3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[[4,4-dimethyl-3R-(2-tetrahydropyr - 33 Example 21 (9S, 11R,13E,15R)-11,16,l6-Trimethyl-lB-(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester By the procedure of Example 8, 11R.16,16-trimethyl-7-fluoro-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoic acid methyl ester was converted to (9S),HR,13E,15R)-n,16,l6-trimethyl-l5-(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester.

Example 22 3,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-l-trans-octenylJ-5R-(2-tetrahydropyranyloxy )-2H-cyclopenta[b]furan-2-one By the procedure of Example 28. 3,3aR,4,5,6,6aS-hexahydro-4R-r3S-(2-tetrahydropyranyloxy)-l-trans-octenylJ-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-one was converted to 3, 3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-l-trans-oetenyl]-5R-(2-tetrahydropyranyloxy)-2H-eyelopenta[b]furan-2-one.

Example 23 3,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-l-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta(b]furan-2-one By the procedure of Example 6 3,3aS,4,S,6,6aS-hexahydro-3-fluoro-4R-(3S-(2-tetrahydropyranyloxy)-l-trans-octenylJ-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta(b]furan-2-one was converted to 3,3as,4.5,6,6aS-hexahydro-352389 -34-fluoro-4R-[3S-(2-tetEahydEopyranyloxy)-l-trans-octenyl]-5R {2-tetrahydropyranyloxy)-2H-cyclopenta[b]fuEan-2-ol.

Example 24 11R,15S-Di-(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxy prosta-cis-5-trans-13-dienoic acid methyl eetec By the procedure of Example 7, 3.3as.4,5.6.6aS-hexahydro-3-fluoro-4R-[3S-(2-tettahydEopyranyloxy)-l-tEans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-ol was converted to llR,15S-di-(2-tetrahydro10 pyranyloxy)-7-fluoro-9S-hydEOxy-prosta-cis-5-tEane-13-dienoic acid methyl ester.

Example 25 (9S.llR.l3E,15S)-ll,15-Di-(2-tetrahydEopyranyioxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester By the procedure of Example 8, 11R.15R-di-(2-tetrahydropyranyloxy )-7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-dienoic acid methyl ester was converted to (9S.11R.13E.15S)-11.15-di-(2-tetrahydropyranyloxy)-6,920 -epoxy-7-fluoro-5-iodo-pcosta-l3-en-l-oic acid methyl ester.

Example 26 (9S,llR.l3E.15S)-11.15-Dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester By the procedure of Example 9, (9S,llR,13E,15S)-ll,l5-di-(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester was converted to - 35 (9S,llR.l3E,15S)-11.15-dihydroxy-6,9-epoxy-7-fluqro-5-iodo-prosta-13-en-l-oic acid methyl ester. 53389

Claims (4)

1. CLAIM

1. ΐ. conpound of the formula wherein R 6 is lower alkyl: R 11 is hydrogen, methyl or 5 -OR 41 , R 2 is methyl, hydrogen or fluoro: R 21 is fluoro, hydrogen, trifluoromethyl or methyl; and X is 41 halogen: -OR is hydroxy or forms a hydrolyzable ether protecting group with the proviso that when R 2 is trifluoromethyl; R is hydrogen or methyl; 10 or an optical antipode or racemate thereof.

2. A compound of the formula given and defined in Claim 1, or an optical antipode or racemate thereof, substantially as hereinbefore described and exemplified.

3. A process for the preparation of a compound of the form15 ula given and defined in Claim 1 or- an optical antipode or racemate thereof, substantially as hereinbefore described and exemplified.

4. A compound of the formula given and defined in Claim 1, or an optical antipode or racemate thereof, whenever prepared 20 by a process claimed in Claim 3,