This invention relates to a novel process for the pre¬ paration of 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor- -PGF2 _Q : esters of the general formula (I)

QH

wherein R stands for saturated or unsaturated straight, branched or cyclic Cι_ ₇ al yl or phenyl or benzyl group. It is known that many prostaglandin derivatives are capable to decrease intraocular tension when used topically, i.e. they are useful for the treatment of glaucoma (pub¬ lished European patent applications Nos. 0,170,258 and 0,253,094). Prostaglandin derivatives possessing particular- ly advantageous effect have been described in the published PCT patent application No. WO 90/02553. From these, the compound of formula (I) proved to be particularly favour¬ able. A method for synthesis of the compound of formula (I) has been disclosed in the PCT application cited above. The aim of this invention is to present an improved method for a synthesis, which is useful for the production of the compound of formula (I) in a good yield, in large amounts, with the desired purity.

It has been found that the compound of formula (I) is obtained in a high purity and in high yield by reducing the oxo group on the side chain of the compound of formula (VII) ,

transforming the obtained 3 , 3a, 4, 5, 6, 6a-hexahydro-2-oxo-4- -[5 * -phenyl-3 ' (R) -hydroxypent-1 • -enil] -5- (4 ' -phenylbenzoyl- oxy) -2H-cyclopenta[b] furan of the formula (VI)

by hydrogenation to 3,3a,4,5,6,6a-hexahydro-2-oxo-4-[5'- phenyl-3' (R)-hydroxy-1 ^« -pentyl]-5-(4'-phenylbenzoyloxy)-2H- cyclopenta[b]furan of the formula (V)

SUBSTITUTESHEET

reducing the compound of formula (V) to 3,3a,4,5,6,6a-hexa- hydro-2-hydroxy-4-[5'-phenyl-3• (R)-hydroxy-1'-pentyl]-5-(4'- phenylbenzoyloxy)-2H-cyclopenta[b]furan of the formula (IV),

removing the protective group from the compound of formula (IV) to obtain 3,3a,4,5,6,6a-hexahydro-2,5-dihydroxy-4-[5*- phenyl-3' (R)-hydroxy-l'-pentyl]-2H-cyclopenta[b]furan of the formula (III)

SUBSTITUTE SHEET

then transforming the compound of formula (III) to give 13,14-dihydro-l5(R)-17-phenyl-18,19,20-trinor-PGF ₂ _* of the formula (II)

by using 4-carboxybutyl-triphenylphosphonium halide and finally, transforming the compound of formula (II) with a compound of the general formula R-X, wherein R has the same meaning as stated above, X is halogen, sulphate, mesyl, tosyl or any other suitable group, to 13 ,l4-dihydro-15(R)- 17-phenyl-18,19,20-trinor-PGF ₂ _ ester of the general for- mula (I) .

The compound of formula (VII) is prepared from phenyl- phosphonium salts and 3,3a,4,5,6,6a-hexahydro-2-oxo-4-(5'- -phenyl-3-oxopent-l'-enyl)-5-(4'-phenylbenzoyloxy)-2H-

SUBSTJTUTESHEET

-cyclopenta[b]furan, which is a known prostaglandin intermediate and can be obtained e.g. according to the United States patent specification No. 3,778,450. Other reagents used are commercially available. The reduction of the compound of formula (VII) to the compound of formula (VI) is carried out by using any reagent known suitable for the reduction of enones especially from the chemical literature of prostaglandins, e.g. by using lithium tri(sec-butyl)borohydride or sodium borohydride [J. Am. Chem. Soc. 94., 8616 (1972); J. Am. Chem. Soc. 106. 6717 (1984)]. The transformation of the compound of formula (VI) to the substances of formula (V) may be realized in the pre¬ sence of a catalyst commonly used for hydrogenation, for example palladium on carbon or rhodium on carbon but prefer- ably palladium on carbon, preferably in the presence of a base or sodium salts like sodium hydroxide or sodium nitrite. The transformation of the compound of formula (III) to a compound of formula (II) may be carried out by using any combination of conditions (base, solvent and the like) com- monly used in the Wittig reaction. Preferably sodium amid, potassium terc.butylate, sodium hydride or buthyl lithium as a base and diglyme, DMSO, DMF or tetrahydrofurane as a sol¬ vent can be used. The transformation of the compound of for¬ mula (V) to the compound of formula (IV) and subsequently, the transformation of the compound of formula (IV) to the product of formula (III) can be achieved without isolating the compound of formula (IV) , too, under suitably selected conditions. It is obvious to a man skilled in the art that

SUBSTITUTE SHEET

the compounds of the formula (II-VII) and the general for ^¬ mula (I) may contain further substituents and the claimed process still takes place. Such reactions are therefore clearly within the scope of this patent application. ,ve summarize our process on the following Scher.e I.

The process of the invention is illustrated in detail by the following non-limiting Examples. Example l

Preparation of 3,3a,4,5,6,6a-hexahydro-2-oxo-4-(5'- 5 -phe^l-a-oxo-pent-l'-enyl)-5-(4'-phenylbenzoyloxy)-

-2H-cyclopenta[b]furan [compound of the formula (VII)] A solution containing 3,3a,4,5,6,6a-hexahydro-2-oxo-4- -hydroxymethyl-5-(4'-phenylbenzoyloxy)-2H-cyclopenta[b]furan (18 g, 51 mmol) in dry toluene (110 ml) is cooled to 18 °C, 10 then the solution of dicyclohexylcarbodiimide (18 g, 83 mmol) and 1 Molar phosphoric acid solution (8 ml, 8 mmol) in dry dimethylsulfoxide is added. The reaction mixture is maintained below a temperature of 25 °C under continuous cooling. After 30 minutes, the following reagents are added 15 to the reaction mixture in intervals of 30 minutes:

1 M phosphoric acid solution (4 ml) in dimethyl¬ sulfoxide; dicyclohexylcarbodiimide (9 g, 41 mmol) and 1 M phosphoric acid solution (5 ml) in dimethylsulfoxide.

Subsequently, the reaction mixture is stirred at 20-22 20 °C for 2 hours. Meanwhile triphenyl-(4-phenyl-3-oxobutyl)- phosphonium iodide (27.3 g, 50 mmol) and 5 M calcium hydr¬ oxide solution (10 ml) in toluene (250 ml) are stirred at 45 °C for 90 minutes; then the solution obtained is washed 3 times with 100 ml of water each of 45-50 °C temperature, un- 2. til neutral, then toluene (45 ml) are removed from the sol¬ ution under reduced pressure. The residual solution is added to the other reaction mixture at a rate that its temperature does not exceed 30 °C. After 2 hours the solution is

S -

_ .__

- 8 -

heated to 35 °C, after additional 1 hour concentrated hydro¬ chloric acid (4 ml) dissolved in water (30 ml) are added and then stirred for 1 additional hour. The precipitate is removed by filtration, the filtrate is washed with toluene and after combination, the toluene solution is washed with water (150 ml) , 4 times with saline (30 ml) , dried over an¬ hydrous sodium sulfate and then evaporated to 350 ml.

The above solution is transferred to a column contain¬ ing silica gel (135 g) and toluene and eluted by using an 5:1 mixture of toluene and ethyl acetate. After evaporating the solution, dark brown solid (21 g) are obtained which is dissolved in boiling methanol (840 ml) . After cooling the solution to 0 °C, filtering the precipitate and washing with cold methanol (30 ml) , the product is dried at room te pera- ture to give the title product of formula (VII) as a white substance in a yield of 12.0 g (48.7 %) , m.p.: 129-130 °C, [°UD ⁼ -145° (c — 1, ethyl acetate) . Example 2

Preparation of 3 3a _/ 4,5 _/ 6,6a-hexahydro-2-oxo-4-(5 ^l - -phenyl-3-oxo-pent-l'-enyl)-5-(4'-phenylbenzoyloxy)-

-2H-cyclopenta[b]furan [compound of the formula (VII)] a) To a solution of 3,3a,4,5,6,6a-hexahydro-2-oxo-4- hydroxymeth l-5-(4'-phenylbenzoyloxy)-2H-cyclopenta[a]furan (27 kg) in toluene (165 L) , cooled to 17 °C, dicyclohexyl- carbodiimide (DCC) (27 kg) , phosphoric acid in dimethyl¬ sulfoxid (DMSO) 1M (12L) was added. The temperature of the reaction mixture was kept below 25 °C after 60 min. The following reagents in the following orders were added to the

reaction mixture in 60 min. intervals; phosphoric acid in DMSO 1M (6L) , DCC (13.5 kg), phosphoric acid in DMSO 1M (6L) . The reaction mixture was stirred at 20-25 °C for additional 7 hours (TLC monitoring) . TLC Rf = 0.32 (silicagel, AcOEt:toluene)

(silicagel, toluene-AcOEt-AcOH: 30:15:2) b) Triphenyl-2-oxo-4-phenylbutylphosphonium iodide (38.4 kg), potassium hydroxide (5 kg) in water (105L) , toluene (210L) and dichloromethane (90L) was stirred vigo- rously for 3 hours followed by addition of sodium chloride (5 kg) . The organic layer was separated and washed with brine (3xll3L) , dried on sodium sulphate, concentrated in vacuo to 70L, this solution was added to the solution pre¬ pared by the method described in part a) of this example at a rate that the temperature of the reaction mixture not ex¬ ceed 25 °C. After 7 hours the solution was cooled to 18 °C (TLC monitoring) . A solution of concentrated HCL (6L) in wa¬ ter (45L) was added and the mixture was stirred for an hour. The precipitate was removed by filtration, washed with tolu- ene (2x45L + 2x23L) . The organic layer was washed with water

(225L) and brine (4x45L) , the water solution was extracted with toluene (2x23 + 1x30L) , the organic layers were collected and dried on sodium sulphate (15 kg) , filtered, washed with toluene (2xl5L) , and evaporated in vacuo to 85L and added methanol (240L) , coc \ό\ to 0 °C, filtered, washed with methanol:toluene 9:1 (49L) and methanol (98+60L) to give a white crystalline product, mp: 129-130 °C, (yield 19.4 kg, 52.7 %), [α] _D ²⁰ = -116° (c = 1.26, CH ₃ CN) .

Example 3

Preparation of 3,3a, .5,6,6a-hexahydro-2-oxo-4-[5*- -phenyl-3• (R)-hydroxypent-l'-enyl]-5-(4'-phenyl¬ benzoyloxy)-2H-cyclopenta[b]furan [compound of the 5 formula (VI)]

A mixture containing 1.04 M lithiu -tri(sec-butyl)- borohydride (418 ml, 0.434 mol) in tetrahydrofuran solution and dry diethyl ether (420 ml) is cooled to -130 °C. The compound of formula (VII) (200 g) are dissolved in tetra- 10 hydrofuran (1000 ml) and diethyl ether (900 ml) , cooled to - 130 °C and added to the above borohydride solution during 1 minute. After 5 minutes the reaction mixture is poured into a mixture containing water (5.5 1), 2 M sodium sulfate sol¬ ution (250 ml) and saline (500 ml) and stirred at room tem- 15 perature for 15 minutes. The solution is successively washed with water (2 L) , ethyl acetate (1 L) and twice with saline (200 ml) each, dried over anhydrous sodium sulfate and evap¬ orated under reduced pressure. The liquid residue obtained is transferred to a column containing silica gel (5 kg) . 20 After eluting with a 7:1 mixture containing methylene chloride and ethyl acetate and recrystallizing the product obtained from the mixture of ethyl acetate (80 ml) , diiso- propyl ether (160 ml) and hexane (80 ml) , white, crystalline title compound of formula (VI) (69.7 g) are obtained, m.p. : 25 129-130 °C, [α] _D = -108° (c = 1, ethyl acetate).

^S UBSTITUTE SHEET

Example 4

Preparation of 3,3a,4,5,6,6a-hexahydro-2-oxo-4-[5'- -phenyl-3* (R)-hydroxypent-l*-enyl]-5-(4•-phenyl¬ benzoyloxy)-2H-cyclopenta[b]furan [compound of the 5 formula (VI)]

To a stirred suspension of enone of the formula (VII) (19.3 kg) in methanol (4.5L) and chloroform (200L) , cooled to -3-5 °C sodium borohydride (2.38 kg) was added (TLC moni¬ toring) . The reaction mixture was poured into water (20L) 10 followed by addition of cone. HCl (12.6L). The mixture was dried on Silicagel (30 kg) , filtered, w shed with chloroform (60+30L) . The organic layer was concentrated to 60L and chromatographed on two columns. Both columns were packed with silicagel (135 kg) and toluene (300L) . Toluene: _ OEt 15666L:133L + (250L:150L) and AcOEt 250L were used successive¬ ly as eluent, for both columns. Fraction V (410L) was concentrated in vacuo to 35L. To the residue diisopropyl ether (90L) was added, cooled to 0 °C/-5 °C, stirred for an hour. The white crystalline product was filered and washed 20 with DIPE- AcOEt 3:1 (16L) . Yield 7.38 kg (38%). TLC:Rf = = 0.5 (silicagel; AcOEt) (0.36 (AcOEt:hexane 1:1) [α] = = -101.59 (c = 0.69 CH3CN) . Example 5

Preparation of 3 _/ 3 _, 4 _, 5 _, 6,6a-he ahy ro-2-o o-4-[5 ^, - 25 -phenyl-3' (R)-hydroxy-l'-pentyl]- '4'-phenyl¬ benzoyloxy)-2H-cyclopenta[b]furan pound of the formula (V)] To a solution containing -3,3a,4,5.6,6a-hexahydro-2-

SUBSTITUTESHEET

-oxo-4-[5'-phenyl-3 ^• (R)-hydroxypent-1*-enyl]-5-(4*-phenyl- -benzoyloxy)-2H-cyclopenta[b]furan (70 g, 144 mmol) in ethanol (2 L) at 18-20 °C, palladium-on-carbon catalyst (7.0 g) and sodium nitrite (3.5 g, 50 mmol) as a suspension in water (100 ml) are added. The mixture is stirred under hydrogen of 5 bar pressure for 90 minutes, then the catalyst is filtered off, 1 M hydrochloric acid solution (100 ml) are added and the mixture is stirred at room temperature for 1 hour. After removing the solvent under reduced pressure the oily residue obtained is dissolved in ethyl acetate (700 ml) . The aqueous phase is twice extracted with ethyl acetate (200 ml) each and the combined ethyl acetate solution is twice washed with saline (100 ml) each. After drying over anhydrous sodium sulfate and evaporating the solvent, the title compound of formula (V) is obtained as an oily residue in a yield of 95 % with an Rf value of 0.23 (developing sys¬ tem hexan/ethyl acetate 1:1), [α.]-_. = -66° (c = 1, ethyl ace¬ tate) . IR spectrum (taken on a Zeiss Specord M-80 type spectrometer) (KBr, cm ^-1 ): 3500 (OH), 3080, 3020 (CH aroma- tic), 2940, 2860 (CH aliphatic), 1770, 1710 (C=0) , 1610, 1500 (aromatic ring vibration), 1290, 1190, 1100 (C-O-C) , 850 (p-subst. aromatic) , 750, 700 (monosubst. aromatic) . Example 6

Preparation of S _/ Sa^S _/ β _/ ea-hexahydro-Σ-oxo^-^'- -phenyl-3* (R)-hydroxy-l ¹ -pentyl]-5-(4'-phenyl¬ benzoyloxy)-2H-cyclopenta[b]furan [compound of the formula (V)] To a solution of the compound of the formula (VI) (7.2

SUBSTITUTESHEET

kg) in ethanol abs. (2C L) at 15-20 °C a suspension of 10 % Pd/C (1.4 kg) and sodium nitrite (0.72 kg) in water (36L) was added. The solution was stirred under hydrogen atmos¬ phere (1200 kbL) for 3 hrs (TLC monitoring). 2M HCl (105L) was added and stirred at room temperature for 1 hour. The catalyst was removed by filtration, washed with ethanol abs. (20 L) . The solvent was removed in vacuo to 50L. The result¬ ing oil was dissolved in toluene (140L) , washed with brine 15% (3x30L) . The water phase was washed with toluene (20L) . The combined organic extracts were dried on sodium sulphate (10 kg) and sodium hydrogen carbonate (0.5 kg), respective¬ ly, filtered. The precipitate was washed with toluene (30L) . The solvent was removed in vacuo to have a residue (90L) which was used directly for the next step. The residue con- tains the compound of the formula (V) (7.03 kg, 96.7 %) . Example 7

Preparation of 3,3a,4,5,6,6a-hexahydro-2-hydroxy-4- -[5'-phenyl-3' (R)-hydroxy-1'-pentyl]-5-(4•-phenyl¬ benzoyloxy)-2H-cyclopenta[b]furan [compound of the formula (IV)]

After dissolving 3,3a,4,5,6,6a-hexahydro-2-oxo-4-[5'- -phenyl-3• (R)-hydrσxy-1'-pentyl]-5-(4•-phenylbenzoyloxy)-2H- -cyclopenta[b]furan (65.7 g,135 mmol) in dry tetrahydrofuran (330 ml) , diisobutyl aluminium hydride (150 ml, 297 mmol) in dry hexane solution (150ml) are dropwise added at a terr ra- ture between -65 °C and -75 °C. After stirring the reaction mixture for 10 minutes, the solution is poured into the mix¬ ture of water (1 L) and 2 M sodium hydrogen sulfate solution

SUBSTITUTE SHEET

(500 ml) and stirred for 30 minutes. The solution is washed with ethyl acetate (1 liter and than twice with 500 ml) each, then the combined organic phase is twice washed with saline (200 ml) each. After evaporating the organic phase under reduced pressure, the title product of formula (IV) is obtained as a colourless oily residue which is used without purification in the next step, Rf = 0.25 (benzene/ethyl acetate 1:1) .

Example 8 Preparation of 3,3a,4,5,6,6a-hexahydro-2-hydroxy-4- -[5'-phenyl-3• (R)-hydroxy-1'-pentyl]-5-(4•-phenyl¬ benzoyloxy)-2H-cyclopenta[b]furan [compound of the formula (IV)]

A solution of diisobutylaluminium hydride (DIBAL) (9.1 kg) in dry toluene (31 L) was added to a stirred solution of the compound of formula (V) (6.8 kg) in toluene (70L) at -72/-80 °C, after 1 hour (TLC monitoring) ethyl acetate (5L) was added, followed by addition of sodium hydrogen sulphate 1M (240L) . The organic layer was separated and dried on sodium sulphate (9 kg) , filtered, washed with toluene; AcOEt (5L:5L) . The water layer was washed with AcOEt (3x35L) . The organic layers were collected and dried with sodium sulphate (9 kg), filtered, washed with toluene: AcOEt 1:1 (40L) . The organic layers were collected and toluene (100L) , triethyl- amine (0.5L) were added to stabilise the triol. The solution of the triol was chromatographed on silicagel (34 kg) packed on toluene (60L) , using toluene:AcOEt (1:1) (400L) and AcOEt (560L) respectively as eluent,the following fractions in the

SUBSTITUTE SHEET

following order were collected; fraction I (50 L) , fractions II and III (400L) each, fraction IV (230L) . Fraction III was rich of the desired product. The solvent was removed in vacuo. To the residue (20 L) diisopropyl ether (DIPE) (65L) was added, cooled to 0 °C. A solid substance was formed, filtered and washed with DIPE:AcOEt 3:1 (2xlOL) to give a white crystalline product yield (2.8 kg, 63.1 %) . Excess of DIBAL have been used to remove the PPB while the compound of the formula (V) was reduced to compound of the formula (IV) . Example 9

Preparation of 3,3a,4,5,6,6a-hexahydro-2,5-dihydroxy- -4-[5'-phenyl-3' (R)-hydroxy-l'-pentyl]-2H-cyclo- penta[b]furan [compound of the formula (III)] A mixture containing 3,3a,4,5,6,6a-hexahydro-2-hydroxy- -4-[5--phenyl-3' (R)-hydroxy—1'-pentyl]-5-(4'-phenylbenzoyl¬ oxy)-2H-cyclopenta[b]furan (65.2 g, 133.4 mmol), potassium carbonate (19.0 g, 133.4 mmol) and methanol (330 ml) is stirred at 40-45 °C for 5 hours, then cooled to 0 °C and the pH value is adjusted to 7-8 by the slow addition of 1 N phosphoric acid solution. After filtering off the preci¬ pitate, the filtrate is washed twice with water (70 ml) each and then twice with a 2:1 mixture of methanol (30 ml) and water each.

After adding saline to the filtrate and extracting four times with ethyl acetate (250 ml) each, the combined organic phase is washed with saline, dried and evaporated under reduced pressure. The solid obtained is dissolved in ethyl acetate (100 ml) at 60 °C, diisopropyl ether (100 ml) are

— —

added to the solution, cooled to room temperature and then hexane (200 ml) are slowly added. After stirring the mixture at 0 °C, the crystalline precipitate is filtered, washed twice with a 2:1 mixture of diisopropyl ether (30 ml) and 5 ethyl acetate each and dried to give white crystalline title compound (35.93 g, 87.90 %) of formula (III), m.p.: 103-106 °C, [α]o = -47° (c = 1, ethyl acetate) .

IR spectrum (taken on a Zeiss Specord M-80 type spectrometer) (KBr, cm" ¹ ): 3380 (OH), 3030 (CH aromatic) , 2980, 2960, 10 2920, 2860 (CH aliphatic), 1600, 1590, 1570, 1500 (aromatic ring vibration), 1090 (C-O-C) , 1000 [C-O-(H)], 750, 700 (monosubst. aromatic) .

^- spectrum (taken on a Bruker WP 80 device, CDCI ₃ , TMS standard, δ ppm) : 7.23 (s, 5H, aromatic H) , 5.64, 5.51 (d, 5 1H, 3-H),4.63 (l, 1H, 1-H),3.90 (1H, 7-H) , 3.60 (1H, 3'-H). The product is an 1:1 mixture of the exo and endo isomers.

Example 10

Preparation of 13,14-dihydro-15(R)-17-phenyl-18,19,20- 0 -trinor-PGF ₂ α [compound of the formula (II)]

4-carboxybutyl-triphenylphosphonium bromide (147.2 g, 3.32 mmol) and potassium tert-butoxide (186g, 1.66 mmol) are addedto a solution of 3,3a,4,5,6,6a-hexahydro-2,5-dihydroxy- -4-[5'-phenyl-3* (R)-hydroxy-1 ¹ -pentyl]-2H-cyclopenta[b]furan 5 (33.9 g, 110.7 mmol) [compound of the formula (III)] in tetrahydrofuran (500 ml) and the solution is cooled to -25 °C. The mixture is stirred first at -20 °C, then at 0 °C altogether 6 hours, then the pH is adjusted to 8-9 by adding

2 M aqueous sodium hydrogen sulfate solution and tetrahydro- furan is distilled off under reduced pressure. After adding water (200 ml) to the residue, the mixture is cooled to room temperature, the precipitate is filtered, washed twice with saturated sodium hydrogen carboate solution (200 ml) each and then twice with water (100ml) each. The combined aqueous phase is washed twice with methylene chloride (150 ml) each, the pH value is adjusted to 3-4 by ing sodium hydrogen sulfate solution and then extracted ce with ethyl acetate (500 ml) each. The combined ethyl acetate phase is twice washed with saline (100 ml) each and evaporated. The thick, liquid suspension is shaken with acetone (100 ml) for 10 minutes, the precipitate is filtered, washed 6 times with 100 ml of 40:25 (by volume) mixture of diisopropyl ether and aceton each and the filtrate is evaporated under reduced pressure to obtain the title compound of the formula (II) as an oily residue in a yield of 85 %, which can be transformed to the compound of formula (I) without purification. Example 11 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinor- l-PGF ₂ α [compound of the formula {II)]

To a stirred suspensic of 4-carboxybutyl triphenyl phosphonium bromide (5.32 kg) in ϊ. F (40L) under nitrogen at 0-5 °C potassium butoxide (4.49 k wa ^dded, and stirred for 20 in. at room temperature. the asultant red orange solution of ilyde at -15/-10 °C the compound of the formula (III) was added (1.23 kg) in THF (8L) , the mixture was stirred for 4-7 hours (TLC monitoring) . The reaction mixture

SUBSTITUTE SHEET

was diluted with water (25L) , washed with toluene (25L) , the organic phase was separated. The water layer was washed with chloroform (3x6L) , acidified with sodium hydrogen sulfate 2M (15L) , extracted with AcOEt (18L and 22x6L) successively. The organic layer was washed with 15 % sodium chloride solu¬ tion (2x6L) , dried on sodium sulphate (0.4 kg), filtered. The precipitate was washed twice with AcOEt (4L) . The sol¬ vent was removed in vacuo, the slurry was shaken with DIPE: :acetone 2:1 (18L) to crystallize the byproduct triphenyl- phosphoxide which was removed by filtration, washed with DIPE:acetone 1:1 (4x3L) . The organic layer was concentrated in vacuo to give the compound of the formula (II) which is used directly without isolation for the next step. Example 12 Preparation of l3,14-dihydro-l5(R)-17-phenyl-18,19,20- -trinor-PGF ₂ c_ isopropyl ester [compound of the formula (I)]

After adding anhydrous potassium carbonate (22.95 g) and isopropyl iodide (37.55 g, 221.4 mmol) to the solution of crude 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2 _α in 200 ml of dry dimethylformamide (50.64 g, 110.7 mol) ob¬ tained in Example 6, the mixture is stirred at 50 °C for 5 hours, then the reaction mixture is poured to a mixture of water (900 ml) , 2M sodium hydrogen sulfate solution (120 ml) and ethyl acetate (500ml) .The aqueous phase is extracted with additional ethyl acetate (500ml) .The combined ethyl acetate phase is successively washed twice with 2% lithium chloride solution (500 ml) each, saturated sodium hydrogen carbonate

SUBSTITUTESHEET

solution (100 ml) and twice with saline (200 ml) each, dried and ethyl acetate is evaporated under reduced pressure. The oily residue is purified by chromatography on silica gel (1 kg) containing silicon gel by using a 20:1 mixture of methylene chloride and isopropanol as eluent, then on silica gel (900 g) by using an 1:1 mixture of ethyl acetate and hexane as eluent to obtain after evaporation colourless oily title compound (16 g) of the formula (I) , Rf = 0.42 (diisopropyl ether/acetone/water 40:25:1), [α]β = +34° (c = 1, acetonitrile) .

IR spectrum (taken on a Zeiss Specord M-80 type spectro¬ meter, by using the liquid film method between NaCl sheets) ( cm" ¹ ): 3400 (OH), 3060 (CH aromatic) , 2990, 2930, 2860 (CH aliphatic), 1730 (C=0) , 1600, 150 (aromatic ring vibration), 1110 (C-O-C) , 750, 700 (monosubst. aromatic) .

^■ --H-NMR spectrum (taken on a Bruker AC 400 device, CDCI ₃ , TMS inner standard, δ ppm) :

7.24 (s, 5H, aromatic H) , 5.44 (dd, 1H, 6-H) , 5.41 (dd, 1H, 5-H) , 4.99 (m, 1H, -CH- isopropanol), 4.17 (s, 1H, 9-H) , 3.94 (s, 1H, 11-H) , 3.66 (m, 1H, 15-H) . Example 13

Preparation of I3,14-dihydro-i7-pb_nyl-18,l9,20-trinor PGF ₂ α isopropyl ester

[Compound of the general formula (I), wherein R is isopropyl group]

To the crude product of the formula (II) dissolved in DMF (6L) , potassium carbonate (1.24 kg) and isopropyl iodide (1.15 L) were added, and the mixture was warmed to 45-50 °C

S' UBSTΓΓUTE SHEE-

over a period of 5-7 hours at which time the reaction was completed (TLC monitoring) . The mixture was diluted with water (2.8L), acidified to pH 2-3 with sodium hydrogen sulphate 1M (13L) . The water layer was extracted with AcOEt:hexane 3:2 (3x9L) , wherupon the organic layer was washed with water (2x4L) and dried over sodium sulphate (1.5 kg) filtered. The precipitate was washed with AcOEt (2X1.5L), concentrated in vacuo, furnishing the target com¬ pound as a light brown oil. The crude oil (2.7 kg) was subjected to a column chromatography twice on silicagel.

The crude oil was dissolved in DIP:acetone 3:1 (6L) and chromatographed on silicagel (70 kg) using DIPE:acetone 3:1 (1200L) , as eluent, and five fractions were collected in the following order; I (280) , II (50) , III (10) , IV (270) and V (70L) respectively. Fraction IV was containing the major amount of the product (TLC monitoring) which was concentrat¬ ed in vacuo. The resulting oil was dissolved in dichloro- methane (6L) and chromatographed on silicagel (20 kg) using a gradient elution with dichloromethane (20L) and dichloro- methane:isopropanol 40:1 (61.5L), 30:1 (20.7L) and 5:1 (60L) successively. Five fractions were collected in the following order; I (127L) , II (0.5L), III (0.5L), IV (12L) and V (5L) respectively. The purity of the fractions were investigated with TLC and HPLC. Fraction IV was found to be pure. The solvent was removed in vacuo, the yellowish oil was treated with active carbon (0.11kg) in isopropanol (6.2L), filtered, washed with isopropanol (2x0.56L) .The solvent was removed in vacuo (0.2 bar) at 40-50 °C to give the target compound as

SUBSTITUTESHEET

pure colourless to slightly yellowish oil yield (0.96 kg, 55.5 %) .

Example 14

Preparation of 3,3a,4,5,6,6a-hexahydro-2,5-dihydroxy-4- _.[5•-phenyl-3•-(R)-hydroxy-1'-pentyl)-2H-cyclopenta[b]- furan [compour of the formula (III)]

A solution containing 3,3a,4,5,6,6a-hexahydro-2-oxo-4- -[5'-phenyl-3 ^■ (R)-hydroxy-l'-pentyl]-5-(4*-phenylbenzoyloxy- -2H-cyclopenta[b]furan (6.8 g, 14 mmol) in anhydrous toluol (82 ml) is cooled to -80 °C and diisobutyl aluminum hydride (9.1 g, 64 mmol) dissolved in of anhydrous toluene (31 ml) are dropwise added under cooling. The reaction mixture is stirred at a temperature between -70 °C and -80 °C until the reaction becomes complete (about 1 hour) . Then, the reaction mixture is poured into IM sodium hydrogen sulfate solution (204 ml) , stirred for 45 minutes and after separating the phases the product remained in the aqueous phase is extracted into ethyl acetate. After combining, the organic phase is dried over anhydrous sodium sulfate and then transferred to a column prepared from silica gel (34 g) and toluene (60 ml) . The aimed product is eluted with a mixture of toluene and ethyl acetate. The fraction containing the pure product is evaporated to a volume of 20-25 ml and the product is crystallized by using diisopropyl ether (65 ml) . The product obtained is washed by a mixture of diisopropyl ether and ethyl acetate to give the title product (2.8 g) of formula (III), m.p.: 103-106 °C.

^S UB ^S TITUTE SHEET