GB2129796A - Preparation of aminocyclopentane acids - Google Patents

Description

1 1 : 1 GB 2 129 796 A 1

SPECIFICATION

Preparation of arninocyclopentane acids This invention concerns the preparation of aminocyclopentane acids and particularly the preparation of 5 0-hydroxy compounds of the general formula (1) 0112 (1) (CH 2)2 X WCOOH 10 Ho Y wherein W is straight or branched C1-7 alkylene; 15 X is cis or trans -CH=CH- or -CH2CH2-; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -0-, -S-t - S02-, or -NR3 (where R' is a hydrogen atom, Cl-7 alkyl or aralkyl having a C14 alkyl portion); and/or (b) is optionally substituted by one or more C1-4 alkyl groups; and R2 is (i) straight or branched Cl-5 alkyl substituted by (a) phenyl [optionally 20 substituted by C1-6 alkyl, C5-7 cycloalkyl, phenyl (optionally substituted by C1-4 alky], C1-4 alkoxy or phenyl)], (b) thienyl [optionally substituted by C1-6 alkyl, C1-6 alkoxy, C5-7 cycloalkyl or phenyl (optionally substituted by Cl-3 alkyl, C1-3 alkoxy or halogen)], or (c) naphthyl (optionally substituted by C1-4 alkyl or C1-4 alkoxy), or (H) cinnamy] and the physiologically acceptable salts and solvates (e.g. hydrates) thereof.

The structural formulae herein are to be understood to include the enantiomers of each of the compounds 25 concerned as well as mixtures of the enantiomers including racemates, even though the precise structure as set out only relates to one enantiomer.

The compounds of formula (1) are described in British Patent Specification 2097397A. They have shown endoperoxide and thromboxane antagonist activity and are therefore of interest in the treatment of asthma and cardiovascular diseases.

The process of the invention is particularly applicable to the preparation of compounds of formula (1) as defined below.

The amino group Y enables the compounds of formula (1) to form salts with inorganic or organic acids, e.g. hydrochlorides and maleates. Salts may also be formed with bases, and examples of such salts are alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium, substituted 35 ammonium (e.g. tromethamine or dimethylaminoethanol), piperazine, N,N- climethylpiperazine, morpholine, piperidine and tertiary amino (e.g. trimethylamine) salts.

The heterocyclic amino group Y may for example have a 5,6 or 7-membered ring e.g. pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1,1- dioxothiamorpholino, homomorpholino and hex amethyleneimino. Examples of the optional substituents (R 3) which may be present on a second nitrogen 40 atom in the ring are methyl, ethyl, butyl, hexyi, benzyi, and phenethyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl, ethyl or buty]. Y is preferably a morpholino or piperidino group.

When R' is a substituted alkyl group, the alkylene portion may for example contain 1-3 carbon atoms (e.g.

methylene, ethylene or propylene) and is preferably a methylene group.

In R 2 groups of the type (i) (a),thephenyl group may besubstituted by, forexample, methyl, ethyl, t-butyl, cyclohexyl, benzyi, phenethyl, or phenyl (optionally substituted by methyl, ethyl, methoxy or butoxy) groups.

In R2 groups of the type (i) (b), the thienyl group may be substituted by, for example, methyl, ethyl, methoxy, ethoxy, cyclohexyl or phenyl (optionally substituted by methyl, ethyl, methoxy, ethoxy, chloro or 50 bromo) groups.

R 2 is preferably a benzyi group in which the phenyl group is substituted by thienyl or phenyl (which phenyl group itself may be optionally substituted by C1-4 alkyl or C1-4 alkoxy); or cinnamyi.

Particularly preferred R 2 groups are benzy] groups in which the phenyl portion is substituted (preferably in the para-position) by a phenyl, tolyi or methoxyphenyi group.

X is preferably cis -CH=CH-. W may for example contain 1-5 carbon atoms in a straight or branched chain, and is preferably -CH2CH2_.

In general, the compounds of formula (1) in which the carbon atom carrying the -(CH2)2XWCOOH group is in the R-configuration (and mixtures containing this isomer) are preferred, i.e. the 1 R-isomers.

Thus, particularly preferred compounds of formula (1) are those in which W is -CH2CH2-, X is CiS -CH=CH-, Y is morpholino or piperidino, and R 2 is benzyl in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl, and the physiologically accetable salts and solvates thereof.

Important compounds of this type are [loL(Z),2p,3p,5a]-( )-7-[5-[[(1,1'biphenyi)-4-yilmethoxy]-3-hydroxy2-(4-morpholinyi)cyclopentyll-4-heptenoic acid and its 1 R-Isomer; [la(Z), 2p,3p,5a]-( )-7-[5-[[(1,1'-biphenyi)4-yilmethoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyll-4-heptenoic acid and its 1R-isomer; and the physiolo-65 1 2 GB 2 129 796 A 2 gically acceptable salts and solvates (e.g. hydrates) thereof. The 1 R- isomers of these compounds are particularly important, especially the 1 R-isomer of the hydrochloride salt of the just mentioned piperidinyl compound.

The synthesis of compounds of formula (1) involves a complex multi-stage reaction sequence and British Patent Specification 2097397A describes several possible alternative routes. At some stage, these routes usually include the step of converting an et-hydroxy cyclopentane intermediate into a p-hydroxy cyclopentane intermediate, for example by first oxidising the et-hydroxy compound to form a cyclopenta none and then reducing the latterto form the p-hydroxy compound. It is however also possible to use a sequence where the last step is the epimerisation of the et-hydroxy group of the ot-hydroxy cyclopentane corresponding to the desired product.

In view of the number and complexity of the synthetic routes available, many factors have to be taken into account when considering the production of any particular compound of formu [a (1). It is not only desirable to optimise the synthesis in terms of the yield, physical form and purity of the required product, but also to establish new techniques which can be applied commercially and are thus available for consideration as alternatives to the known methods.

We have now found that compounds of formula (1) can be prepared very satisfactorily by hydrolysing a corresponding ester, amide, nitrile or ortho-ester of formula (2) below. This method has not been suggested before and is advantageous in that the quality and/or yield of the final product can be improved.

We have also found that the compounds of formula (1) are preferably prepared by reducing and subsequently or simultaneously hydrolysing a corresponding cyclopentanone ester, amide, nitrile or 20 ortho-ester of formula (3) as defined below. A particular advantage of this method is that the intermediates and reaction conditions can be chosen so that a separate hydrolysis step is not required and the product is obtained directly in a desirable form.

We have also found that the intermediates of formula (3) are preferably prepared by oxidising the corresponding et-hydroxy cyclopentane ester, amide, nitrile or ortho- ester. In this respect we have thus 25 found that in converting an (x-hydroxy cyclopentane intermediate into the required P-hydroxy product, overall advantages can be obtained by performing the necessary oxidation and reduction steps on a starting material in which the side chain -COOH group is in the modified form of an ester, amide, nitrile or ortho-ester g rou p.

Thus in one aspect the invention provides a process forthe preparation of a compound of formula (1) or a 30 salt or solvate thereof, which comprises hydrolysing a corresponding compound of formula (2) 9R2 1 ACH2)2XWZ H OAV (2) where R2, y, X and W are as defined above and Z is (a) -C02R1 where R' is (1) -CR4R 5 R 6 in which R 4 and R5 are each phenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy, di-(C1-4) alkylamino, nitro or halogen) and R6 is a hydrogen atom or a substituted or unsubstituted phenyl group as defined for R 4 and R5 (2) -SiR 7 R8R9 where R 7, R8 and R9 are aryl (e.g. phenyl) or C1-6 alkyl (3) -CH2CC13 (4) -CH2CH=CH2 (5) -CH(R10)BCH2R11 where B is -0- or -S-, and where W' and W' are -H or C1-4 aikyi (e.g. -CH20CH3, -CH(CH3)OCH2CH3 or -CH2SCH3) or where R10 and C together represent - (CH2)2- or -(CH2)3- (e.g.

tetrahydrofuran-2-yl or tetra hyd ropyra n-2-y1) (b) -CONR2 12 where R12 is H or C1-4 alkyl (c) -CN, or (d) -C(OCH2)3CR 13 where R 13 is C1-4 alkyl.

In a further aspect the.invention provides a process for the preparation of a compound of formula (1) or a salt or solvate thereof, which comprises reducing and simultaneously or subsequently hydrolysing a 55 corresponding cyclopentanone, of formula (3) as defined below. The reduction and hydrolysis steps may be performed as generally described below with respect to the compound of formula (3) and formula (2).

Z is preferably a group (a) (1), for example where R' is triphenyimethyl (in which the phenyl groups are optionally substituted by methyl, methoxy or nitro) or diphenyimethyl (in which the phenyl groups are optionally substituted by halogen, methyl methoxy or dimethylamino). More preferably, R' istriphenyl methyl.

When R' is a group of type (a) (5), it is preferably tetra hyd ropyrany].

The hydrolysis of the derivatives of formula (2) in which Z is a group of the type (a) can in general be effected under acidic or basic conditions, for example in an organic or aqueous organic solvent and at any suitable temperature up to and including reflux.

c 0 1 3 1 GB 2 129 796 A 3 Suitable bases include inorganic bases such as NaOH and KOH. Suitable acids include inorganic acids such as hydrochloric acid and organic acids such as trifluoracetic acid or acetic acid. Suitable solvents for such hydrolyses include tetrahydrofuran, dioxan, ether, aqueous ether, CH2C12. toluene, CH3M and aqueous alcohols.

Esters in which R' is a group (2) may also be removed using a fluoride (e. g. tetra-n-butylammonium fluoride, KF or HR for example using tetrahydrofuran or aqueous CH3M as the reaction solvent.

Esters in which R' is CH2CC13 may also be removed by reduction e.g. with a metal such as zinc under midly acidic conditions for example using an aqueous phosphate buffer. Tetrahydrofuran, dioxan and dimethoxyethane are suitable solvents.

When R' is a group of type (5) and B is S, hydrolysis may also be effected in the presence of Hgl' salts e.g. 10 mercuric trif luoroacetate for example using aqueous CH3M as solvent. These esters may also be hydrolysed in the presence of A911 salts (e.g. A9N03), for example using aqueous tetrahydrofuran, dioxan, dimethoxyethane or CH3M as solvent.

The hydrolysis of the derivatives of formula (2) in which Z is a group of the type (b) or (c) can in general be effected using an inorganic base (e.g. KOH) in a suitable solvent such as aqueous ethanol or ethylene glycol 15 at a temperature up to and including reflux.

The hydrolysis of the derivatives of formula (2) in which Z is a group of the type (d) can in general be effected using mild acidic hydrolysis (e.g. using acetic acid or an acidic phosphate buffer) at a temperature of 5 to 35'C, e.g. room temperature.

The acid of formula (1) produced maybe isolated in the form of a salt, for example a salt with an inorganic 20 acid, such as hydrochloric acid. This is particularly convenient and advantageous when the hydrolysis is effected with the same acid; salt formation and hydrolysis then take place in the same reaction step.

If desired, the free acid may be liberated from a salt initially formed and converted into another salt if required. One salt may be converted into another, e.g. by exchange of cation.

In general, salt formation may be effected in organic or aqueous organic solvents at temperatures of for 25 example O'C to room temperature. Examples of suitable organic solvents are ether, ethyl acetate, CH2C12 and dimethoxyethane.

Salts of inorganic bases may be prepared by adding the base to a solution of the acid of formula (1), e.g. in an aqueous organic solvent. Certain salts may also be prepared by exchange of cation; for example, a calcium salt maybe prepared by addition of a calcium salt (e.g. the chloride or acetate) to a solution of a salt 30 of a compound of formula (1), e.g. an amine or alkali metal salt.

The process of the invention is thus particularly useful in preparing a salt of a compound of formula (1) by treating a compound of formula (2) (e.g. a compound in which Z is a group (a), particularly a group of the type (a) (1), e.g. where R' is tri phenyl methyl) with an acid or a base. Thus for example a hydrochloride of a compound of formula (1) maybe prepared by treating a solution of the compound of formula (2) as just 35 mentioned with hydrogen chloride or hydrochloric acid. This method is particularly suitable in the preparation of the preferred compounds of formula (1) described above.

The compounds of formula (2) may be prepared by reducing the corresponding cyclopentanone of formula (3) OR2 40 (3) (CH2)2XWZ 0 Y 45 In some circumstances, particularly when Z is a group of the type (a) (1) (e.g. trityl), hydrolysis of the compound of formula (2) produced occurs either during reduction or during the isolation of the product, with the advantage that no separate hydrolysis step is necessary. Thus, the compounds of formula (1) are 50 preferably prepared by reducing and simultaneously or subsequently hydrolysing the corresponding compound of formula (3).

The reduction may for example be effected with a selective reducing agent such as diisobutylaluminium 2,6A i-t-butyl-4-m ethyl phen oxide, lithium trisia myi bo rohyd ride, 2, 6-di-tert-buty]-4 methyl phenoxymag nesiu m hyd ride or potassium tri-isopropoxyborohydride, or tri-isobutylalu minium. The 55 reaction temperature maybe from -10'to -78'C. Tetrahydrofuran and toluene are suitable solvents.

The compounds of formula (3) are preferably prepared by oxidising a corresponding oL-hydroxy compound of formula (4) OR2 (CH2)2XVI HO (4) 1 4 GB 2 129 796 A 4 Suitable methods of oxidation are described in British Patent Specification 2075503A.

The compounds of formula (4) in which Z is a group of the type (a) may be prepared by esterification of the corresponding carboxylic acid, i.e. the compound of formula (4) in which Z represents -COOH. Conventional esterification methods may be used.

Thus, compounds of formula (4) in which Z is a group of the type (a) (1), (2),(4) or (5) may thus be prepared 5 by reacting the corresponding carboxylic acid with an appropriate halide R1Hal where Hal represents halogen. The reaction is carried out in the presence of a suitable base, e.g. potassium t-butoxide or a sterically hindered amine such as N,Ndiisopropylethylarnine or triethylamine, in a suitable solvent (such as CH3M, CH2C12 or dimethyisulphoxide), for example at a temperature from O'C to room temperature.

Esters in which R' is -CH2C03 may be prepared by treating a reactive derivative of the corresponding carboxylic acid with CC13CH20H. The reaction may for example be carried out at room temperature using a solvent such as acetone and, where appropriate, in the presence of pyridine.

The reactive derivative is conveniently a mixed anhydride of the acid, formed for example by treatment of the acid with a chloroformate in the presence of a suitable base, e.g. triethylamine or pyridine at -10'C.

The chloroformate may for example be a C1-6 alkyl (e.g. iso-butyl), aryl (e.g. phenyl) or aralkyl (e.g. benzyi) 15 chloroformate.

The parent carboxylic acids required as starting materials in the esterification reactions may be prepared by the methods described in British Patent Specification 2075503A.

Compounds of formula (4) in which Z is a group of the type (b) may be prepared by amidation of the parent carboxylic acid i.e. the corresponding compound in which Z is -COOK Conventional methods for converting acids into amides may be used.

For example, a reactive derivative of the carboxyiic acid may be treated with ammonia or an amine (R 12)2NH in a suitable solvent, e.g. acetone or acetonitrile. The reactive derivative may for example be as described above.

Compounds of formula (4) in which Z is a group of the type (c) or (d) in which X is cis -CH=CH- may be 25 prepared by reacting an aldehyde of formula (5) OR2 CHO HO Y (5) with an appropriate Wittig reagent, e.g. a phosphorane of formula (R 14)3PCHWZ (where R 14 is Cl-6 aikyl or 35 ary], e.g. monocyclic aryl such as phenyl). Suitable reaction solvents include hydrocarbons (e.g. benzene and toluene), ethers (e.g. tetrahydrofuran), dialkylsulphoxides (e.g. dimethyisulphoxide), alcohois and halogen ated hydrocarbons. The reaction may be carried out at any suitable temperature from -70'to 500C, preferably at room temperature. The group X in the product may subsequently be modified as desired.

The preparation of the intermediates of formula (5) is described in British Patent Specification 2075503A. 40

Compounds of formula (2) may similarly be prepared from a corresponding aldehyde of formula (5) in which the ring hydroxy group is in the P-position.

When a specific enantiomer of formula (1) is required, starting materials having the desired stereochemicai configuration should be used in the above processes. Such starting materials may for example be prepared from an enantiomeric bicycloheptenone as described in European Patent Specification 45 74856, using the methods generally described in UK Patent Specifications 2028805A, 2075503A and 2097397A.

The following examples illustrate the invention. Temperatures are in 'C. The following abbreviations are used:

T.I.c. Thin layer chromatography using Si02; PE petroleum ether (b.p. 4060'); THF tetrahydrofuran DIVISO dimethyl sulphoxide Dibal diisobutylaluminium hydride ER ether DIVIF dimethylformamide EA ethyl acetate V' 4 - 0- Chromatography was carried out using silica gel unless otherwise stated. 'Dried' refers to drying with 60 M9S04.'l-lyflo' is a filtration aid.

The preparation of Intermediate 1 is described in British Patent Specification 2075503A.

1 1 GB 2 129 796 A 5 INTERMEDIATE 1 [1R-[1a(Z),20.3c,5otll-(+)-7-[5-[[(1, 1'Biphenyl)-4yllmethoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyll-4heptenoic acid The preparations of Intermediates 2-6 are described in British Patent Specification 2097397A.

INTERMEDIATE 2 [1R-(endo,anti)]-(+)-5-Hydroxy-7-(1-piperidinyl)bicyclo[2. 2. llheptan-2-one INTERMEDIATE 3 jo [1R-(1(Y,2p,3o,5ct)]-(+)-5-[[(1,1'-Biphenyl)-4-yllmethoxy]-3-hydroxy-2(l-p iperidinyl)cyclopentaneacetal- 10 dehyde INTERMEDIATE 4 [1R-[1(x(Z),2p,3p,5cL]j-(+)-7-[5-[[(1, 1'-Biphenyl)-4yllmethoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyll-4heptenoic acid INTERMEDIATE 5 [1R-[1a(Z),2p,3p,5(xll-(+)-7-[5-[[(1, 1'-Biphenyl)-4yljmethoxy]-3-hydroxy-2-(4-morpholin.yl)cyclopentyll-4heptenoic acid INTERMEDIATE 6 [1R-(lct,2p,3p,5a)]-(+)-5-[[(1, 1'-Biphenyl)-4-yllmethoxy]-3-hydroxy-2-(1piperidinyl)cyclopentanepropanol The preparations of Intermediates 7 and 8 are described in British Patent Specification 2108116A.

INTERMEDIATE7 [1R-[lct(Z),2p,3p,5otll-(+)-2-Propenyl 7-[5-[ffl, 1'biphenyl)-4-yljmethoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyll-4heptenoate INTERMEDIATE8 30 [1R-[loL(Z),20,3p,5eLlj-(+)-(Methylthio)methyl7-[5-[[(1, 1'-biphenyl)-4-yllme thoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyll-4heptenoate INTERMEDIATE 9 [1R-(lct,2p,3u-,5oL)]-(+)-5-[[(1, 1'-Biphenyl)-4-yllmethoxy]-3-hydroxy-2(1-piperidinyl)cyclopentanepropanal A solution of Intermediate 3 (13g) in toluene (39mi) was added dropwise to a suspension of potassium 35 tert-butoxide (5.969) in toluene (52mi). Methoxymethyitriphenylphosphonium chloride (1 5.93g) was added and the mixture stirred overnight (18h).

2N Hydrochloric acid (52mi) was added and the mixture heated with stirring at 40'for 30min. Solid K2C03 (13g) was added, the organic phase separated, washed with water (52mi) and dried azeotropically to give a solution of Intermediate 9 in toluene (1 15mi). A portion of the solution (8.8m[), was purified by chromatography eluting with 9:1 EA -methanol to give the title compound as a foam (0.53g).

T.I.c. 4:1 EA- methanol Rf 0.15. [0t123 = +42.8o (CHC13). D INTERMEDIATE 10 [1R-[loL(Z),2p,3ot,5a]]-(+)-7-[5-[[(1, 1'-Biphenyl)-4yllmethoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyll-4heptenoic acid, hydrochloride To a solution of potassium tert-butoxide (21.49g) in toluene (198mi) and THF (52mi) under N2was added 50 3-(ca rboxypro pyi)tri phenyl ph osph on iu m bromide (41.14g). After 1.5h a solution of Intermediate 9 (24.5g) in 50 toluene (220mi) was added and the mixture stirred for 3h. Water (1 25mi) was added, the mixture vigorously shaken and the phases separated. The aqueous phase was washed with toluene (2x225m]) (discarded), then acidified (to pH 7.5) with 2N hydrochloric acid and extracted with CH2C12 (2x225m]). The combined CH2C12 extracts were dried and evaporated to give the title compound, base (24.47g) as a gum. 55 A solution of the base (93mg) in CH2C12 (1.5mi) was treated with an excess of ethereal hydrogen chloride. 55 The solvents were removed and the residual oil triturated with ER (5mi). The resulting solid was filtered, washed with ER and dried to give the title compound (92mg) m.p. 132.5 136' (softens at 128% [OL125 D = +52.9'(CHC13).

INTERMEDIATE 11 [1R-(endo,anti)]-(+)-5-[[4'-Methoxy(l, 1'-biphenyl)-4yllmethoxy]-7-(1-piperidinyl)bicyclo[2.2. llheptan-2-one A mixture of Intermediate 2 (30.51g), benzyltriethylammonium chloride (6.65g) and 4(bromomethyl)-4'methoxy(1,1'-biphenyi)(52.6g) in CH2C12 (365mi) and 17N NaOH (325mi) was vigorously stirred at ambient 65 temperature for 18h. The mixture was diluted withe water (te) and extracted with CH2C12 (3x 150mi). The b 6 GB 2 129 796 A 6 combined extracts were dried and evaporated and the residue was purified by chromatography using ER PE (1: 1 followed by 7:3) as Muent to give the title compound (40.2g). A portion was recrystallised from EA PE m.p. 109. 5-110.50 [0t123.7 = D +22X(CHC13) INTERMEDIATE 12 [1R-(endo,anti)]-(-)-6-[[4'-Methoxy(l, 1'-biphenyl)-4yljmethoxyj-B-(1-piperidinyl)-2-oxabicyclo[3.2. lloctan3-one A solution of peracetic acid in acetic acid (5.6M, 124mi) was added slowly to a stirred mixture of Intermediate 11 (42g) in CH2C12 (235mi), 2N H2S04 (29mi) and water (159mi) and the mixture stirred at ambient temperature for 24h. The mixture was adjusted to ca. pH7 using 5N NaOH and pH 6.5 phosphate buffer then extracted with CH2C12 (3x 200mi). The combined organic extracts were added to an excess of sodium metabisulphite solution and stirred for 24h. The mixture was extracted with EA (1 x 500, 2x250mi) and the combined organic extracts were dried and evaporated and the residue was purified by chromatography using 1: 1 EA-PE as eluent to give the title compound (24.4g). A portion was recrystallised from EA-PE m.p. 116.5-117.5' is [a123.4 = -24.5' (CHCi3) D INTERMEDIATE 13 [IR-(lct,2p,3c,Sot)]-()-3-Hydroxy-5'[[4'-methoxy(l, 1'-biphenyl)-4yljmethoxy1-2-(1-piperidinyl)cyclopentane acetaldehyde DIBAL in hexane (1M, 114mi) was added slowlyto a cold (-70') stirred solution of Intermediate 12 (249) in CH2C12 (240mi). After 0.5h methanol (240mi) was added, slowly at first, and the mixture was stirred at 25 ambient temperature for 16h. The precipitate was filtered off and the filtrate evaporated to give the title compound as a foam (24.1 g).

T.I.c. 9:1 EA-methanol Rf 0.35.

INTERMEDIATE 14 [1R-(lc,2p,3u-,5a)]-(+)-4-[[4'-Methoxy(l, 1'biphenyl)-4-yllmethoxy]-3-(3- methoxy-2-propenyl)-2-(1piperidinyl)cyclopentanol, hydrochloride Asolution of Intermediate 13 (24.1g) in THF (75mi) was added to a cooled (-5to 0% stirred solution of the ylid derived from m eth oxymethyltri phenyl phosphon iu m chloride (78g) and potassium tert-butoxide (25.5g) 35 in THF (800mi). After 1.5h methanol (100mi) was added and the solvents removed in vacuo. The residue in pH6.5 phosphate buffer (600mi) was extracted with CH2C12 (3x 150mi) and the combined extracts were dried and evaporated. The residue was purified by chromatography using 4:1 EA- methanol as eluentto give the title compound, base as an oil (24.8g).

A portion was converted into the hydrochloride salt m.p. 150-1510(dec) [et]23.1 D =38.1'(CHC13) INTERMEDIATE 15 [1R-(1a,2p,3ctS(x)]-(+)-3-Hydroxy-5-[[4'methoxy(l, l,-biphenyl)-4yljmethoxy1-2-(1- piperidinyl)cyclopentanepropanal, hydrochloride Asolution of Intermediate 14 (24.39) in 2N HCl (55mi) and acetone (250m1) was stirred at ambient temperature for 1 h. Most of the acetone was removed in vacuo and the residue in waterwas extracted with CH2C12 (3x150mi). The combined extracts were dried and evaporated to give a solid (23.6g). A portion was triturated with ether to give the title compound as a powder m.p. 182- 185' (dec) [(1122.7 = +51.5'(CHC13) D INTERMEDIATE 16 [1R-[1a(Z),2p,3(Y,5ctll-(+)-Methyl 7-[3-hydroxy-5-[[4'-methoxy(l, 1'biphenYI)-4-yllmethoxYI-2-(1- piperidinyl)cyclopentyll-4-heptenoate, hydrochloride Asuspension of Intermediate 15 (23.6g) in THF (300mi) was addedto theylid derived from 3-(carboxypropyi)triphenylphosphonium bromide (69.5g) and potassium tert- butoxide (36.3g) in THF (1000mi). After 2h water (200mi) was added and the THF was removed in vacuo. The residue was diluted with water (250mi) and extracted with ER (3x 200mi; discarded). The aqueous layer was neutralised using 5N 60 HCl and extracted with CH2C12 (3x200mi). The combined extracts were dried and evaporated and the residue was leftto stand in methanol (250mi) containing concentrated sulphuric acid (5mi) for 19h. Most of the methanol was removed in vacuo and the residue neutralised using 2N NaOH and pH 6.5 phosphate buffer (1 50mi). The mixture was extracted with EA (3x 1 50mi) and the combined extracts were dried and evaporated. The residue was purified by chromatography using initially 9:1 ER-methanol followed by 4:1 65 e . 7 i.

--- --- GB 2 129 796 A 7 ER-methanol as eluent to give the title compound, base as an oil (15.9g). A portion was converted into the hydrochloride salt m.p. 122-1250 (dec).

[CL122.5 = D +55.9' (CH03) INTERMEDIATE 17 [1R,[1(x(Z),2p,3a,5otll-(+)-7-[3-Hydroxy-5-[4'-methoxy(l, 1'-biphenyl)-4-yllmethoxy]-2-(1piperidinyl)cyclopentyll-4-heptenoic acid, hydrochloride A mixture of Intermediate 16 (6.59g), 5N NaOH (7.6mi) and methanol (65mi) was vigorously stirred at ambient temperature for 24h. Most of the methanol was removed in vacuo and the residue in pH 6.5 phosphate buffer (170mi) was extracted with CH2C12 (3x50mi). The combined extracts were dried and evaporated to give a foam (6.4g). A portion of the base in ER-CH2C12 was treated with an excess of ethereal hydrogen chloride to give the title compound m.p. 137- 138.5% 10LID241 = + 51 ' (CH C13) INTERMEDIATE 18 [IR-[lot(Z),2p,3ot,5u-]]-(+)-TriphenylmethyI 7-[5-[[(l, l'-biphenyl)-4- yljmethoxyl-3-hydroxy-2-(lpiperidinyl)cyclopentyll-4-heptenoate Triethylamine (2.49ml) was added to a cold (5') solution of Intermediate 10, base (5.88g) and trityl chloride 20 (4.4g) in CH2CI2 (24ml). The mixture was stirred for 30min then water (60ml) and further CH2CI2 (30ml) added.

The organic phase was separated then evaporated in vacuo. The residue was azeotroped with CH2CI2 (60ml) to give an oil (10.1 3g) which was chromatographed on alumina (500g), eluting with EA to give the title compound as an oi I (5.14g).

T.I.c. (A1203) 49:1 EA-methanol Rf 0.52.

[(X125 = D +34.20 (CHC13) INTERMEDIATE 19 a) [1R-flcL(Z),2p,5oL]]-(-)-Triphenylmethyl7-[5-[[(1,1'-biphenyl)-4yllmethoxy] -3-oxo-2-(1piperidinyl)cyclopentyll-4-heptenoate Triethylamine (9.17mi) was added at 20 to a stirred solution of Intermediate 18 (6.47g) in CH2C12 (65mi), followed by a solution of pyridine/S03 complex (5.75g) in DMSO (65mi). The resulting solution was stirred at 3-5'for 2h and quenched by the dropwise addition of ice-water (65mi). The reaction mixture was extracted with ER (2x65mi) and the extract washed with water (65mi), 1 M citric acid (4x 10mi) and water (10mi). 35 Evaporation of the dried (Na2S04) solvents gave the title compound as a foam (5.9g).

I.r. (CHBr3) 1740cm [0j24 = D -12'(CHC13) The following compounds were prepared in a similar manner:- b)[1R-[1(x(Z),2p,5otjl-(-)-Diphenylmethyl7-[5-[[(1,1'-biphenyl)-4yllmethoxyl-3 -oxo-2-(1piperidinyl)cyclopentyll4-heptenoate, from Intermediate 22. Purification by chromatography using 3:2 ER-PE as eluent.

Analysis Found, C43H47NO4 requires [(X]20 '3 = D -11Y(CHC13) C,80.5; H,7.5; K2.2. C,80.5; H.7.4; N,2.2%.

c) [1R-[1a(Z),2p,5oL]l-(-)-(Methoxymethyl) 7-[5-[[(1, 1'biphenyl)-4yllmethoxy]-3-oxo-2-(1piperidinyl)cyclopentyll-4-heptenoate, from Intermediate 20d. Purification by chromatography using 1:1 ER-PE as eluent.

Analysis Found: Q716; H,8.3; N,2.6. 55 C32H41NO5 requires Q719; H,8.0; N,2.7%.

[0j21 = -14.4'(CHC13) D d) 1R-fla(Z),2pSeLll-O-Triphenyimethyl7-[5-[[4'-methoxy(1,11-biphenyl)-4yllmet hoxy]-3-oxo-2-(1- 60 piperidinyl)cyclopentyll-4-heptenoate, from Intermediate 17. Purification by chromatography using 1:1 ER-PE (b.p. 60-80') as eluent.

T.I.c. 1:1 ER-PE hp. 60-80') Rf 0.29 1 8 GB 2 129 796 A 8 e) [1R-[lct(Z),2p,5ctll-(-)-7-[5-[[(1,1'-BiphenYI)-4-Yllmethoxyl-2-(4morpholin yl)-3-oxocyclopentyll-4heptenamide, compound with ethytacetate (4., 1), from Intermediate 23c. Purification by chromatography using 9:1 EA-methanol as eluent.

Analysis Found: W2.0; M.6; K5.55 5 C29H36N204.0.25C4H802 requires C,72.1; H,7.7; N,5.6%.

[0t]24 = D -11.4(CI-IC13) INTERMEDIATE20 a) [1R-[1(x(Z),20,3PSall-()-Triphenyimethyl7-[5-[[(1,1'biphenyl)-4-yllmethoxy] -3-hydroxy-2-(1piperidinyl)cyclopentyll-4heptenoate Trityl chloride (0.56g) was added to a stirred, ice cooled, solution of the Intermediate 4 (0.376g) in CH2C12 (5mi) containing triethylamine (0. 45mi). After 1.25h the mixture was diluted with pH 6.5 phosphate buffer (50mi) and the product extracted into EA (2x50mi). The EA extract was dried and evaporated in vacuo and 15 the residue was purified by chromatography using 100:1 ER-triethylamine as elueritto give the title compound (0.28g) as a gum.

T.I.c. (A1203) Et20 Rf 0.7 The following compounds were prepared in a similar manner:- b) [1R[la(Z),2p,3p,5a]]-(+)-(Tetrahydro[2H]pyran-2-yl) 7-[5-[[(1, 1'biphenyl)-4-yllmethoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyll-4heptenoate, from Intermediate 4 and 3,4-dihydro[2H]pyran in THF. Purification by chromatography on a] u mina using ER followed by EA and 19: 1 EA-methanol as eluents.

Analysis Found: C35H47NO5 requires [(X120 D = +59'(CI-IC13) C,743; H,8.7; N,2.6. W4.8; MA; M.5%.

c) [1R-[1a(Z),2p,3p,5 11-()-(1-Ethoxyethyl u. --) 7-[5-[[(1, 1'-biphenyl)-4-yllmethoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyll-4-heptenoate, from Intermediate 4 and 1 chloroethyl ethyl ether in THF. Purification by chromatography on alumina using 1: 1 ER-PE as eluent.

Analysis Found: C34H47NO5 requires 1a1D19 = +61.8' (CHC13) C,74.6; H,8.6; N,2.9. C,743; H.8.6; N,2.55%.

d) [1R-flet(Z),2p,3a,,5a]]-(+)-(Methoxymethyl) 7-[5-[[(1, 1'-biphenyl)-4yllmethoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyll-4-heptenoate, from Intermediate 10, base chloromethyl methyl ether and dilsopropylethylamine in DMF. Purification by chromatography using 99:1 EA-Et3N as eluent.

T.I.c. 89:10:1 EA-methanol-Et3N Rf 0.4 [a1D23 = +62.7'(CHCi3) e) [1R-[1a(Z),2p,30,5u-]]-()-(1,1-Dimethylethyl)dimethylsilyl7-[5-[[(1,1'biphe nyl)-4-yllmethoxy]-3-hydroxy2-(4-morpholinyl)cyclopentyll-4-heptenoate, from Intermediate 5 and tertbutyidimethyisilyl chloride. 50 T.I.c. ER Rf 0.31 INTERMEDIATE 21 a) [1R-[lct(Z),2p,5(xll-()-(1,1-Dimethylethyl)dimethylsilyl7-[5-[[(1,1'bipheny li-4-yllmethoxy]-3-oxo-2-(1piperidinyl)cyclopentyll-4-heptenoate Et3N (0.8mi) followed by tert-butyidimethyisily] chloride (0.42g) were added to a cooled (0% stirred suspension of Intermediate 10, camphor sulphonate (1.69) in CH2C12 (7mi). After 0.5h more Et3N (4mi) followed by a solution of pyridine-sulphur trioxide complex (2g) in DIVISO (7mi) were added and stirring was continued for 4h. The mixture was diluted with pH 6 phosphate buffer (100mi) and extracted with ER 60 (2x100mi). The combined extracts were dried and evaporated and the residue was purified by chromatography using 1: 1 ER-PE as eluent to give the title compound as an oil (0.8g).

I.r. (CHBr3) 1735,1705 cm 1 1 9 GB 2 129 796 A 9 The following compound was prepared in a similar manner:- b) [1R-flet(Z),2p,5a]]-()-(1,1-Dimethylethyl)diphenylsilyl7[5-[[(1,1'biphenyl)-4-yllmethoxy]-3-oxo-2-(1piperidinyl)cyclopentyll-4-heptenoate, from Intermediate 10, camphor su 1 phonate using tert5 butyidiphenyisilyl chloride.

I.r. (CHBr3) 1730cm-1 INTERMEDIATE 22 10 [1R-[loL(Z),2p,3c,5otll-(+)-Diphenylmethyl7-[5-[[(1,1'biphenyl)-4-yllmetho xy1-3-hydroxy-2-(1piperidinyl)cyclopentyll-4heptenoate Diphenyidiazomethane (1.1g) was added to a solution of Intermediate 10, base (1g) in CH2C12 (30mi). After 18h at ambient temperature the solvent was evaporated and the residue was purified by chromatography on alumina using 19:1 ER-methanol as eluent to give the title compound as an oil (1. 22g).

Analysis Found:

C43H49NO4 requires [0j20 3 = D +52'(CI-IC13) C,803; H,7.5; K2.6. C,80.2; H,7.7; K2.2%.

INTERMEDIATE 23 a) [1R-[1a(Z),2p,3p,5ctll-(+)-NN-Dimethyl7-[5-[[(1,1'-biphenyl)-4yllmethoxy]-3 -hydroxy-2-(1- piperidinyl)cyclopentyll-4-heptenamide Isobutylchloroformate (0.51 mi) was added to a cold (0') stirred mixture of Intermediate 4, hydrochloride (1 g) and Et3N (1.08mi) in acetone (75mi). After 0.5h dimethylamine (4mi) was added and the mixture left for 25 2h. The mixture was diluted with pH 6.5 phosphate buffer (75mi) and most of the acetone was removed in vacuo. The residue was extracted with EA and the combined extracts were dried and evaporated. The residue was purified by chromatography using 80:20:1 EA-methanol-ammonia as eluant to give the title compound as an oil (0.815g).

I.r. (CHBr3) 3590,1635cm-1 [a123 = +63.2'(CHC13) D The following compounds were prepared in a similar manner:- b) [1R-[leL(Z),20,3pScLll-(+)-2,2,2-Trichloroethyl7-[5-[[(1,1'-biphenyl)4-yllm ethoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyll-4-heptenoate, from Intermediate 4, hydrochloride using 2,2,2-trichloroethanol. Purification by chromatography using 95:5A EA-methanol-Et3N as eluent.

Analysis Found: C32H4OCI3NO4 requires [CL123 = D +59'(CHC13) C,615; H,6.65; N,2.55. Q63.1; H,6.6; N,23%.

c) [1R-[lct(Z),2p,3o,5ctll-(+)-7-[5-[[(1, 1'-Biphenyl)-4-yllmethoxy]-3hydroxy-2-(4-morpholinyl)cyclopentyll4-heptenamide, m.p. 11 1'from Intermediate 1, methane sulphonate and ammonia. Purification initially by chromatography using 7:3 ER-methanol as eluent and then by crystallisation from EA-PE (b.p. 60-80') [(X]22.1 D = +64.2'(CHC13) INTERMEDIATE 24 [lR-[l(x(Z),2p,3p,5otjj-(+)-7-[5-[[(l, l'Biphenyl)-4-yljmethoxyl-3hydroxy-2-(l-piperidinyl)cyclopentyll-4- heptenitrile A solution of Intermediate 6 (1g) in THF (10ml) was added to the ylid derived from 3 cyanopropyltriphenylphosphonium bromide (2.5g) and potassium tettbutoxide (0.69g) in THF (25ml). After 1 h water (100ml) was added and the mixture extracted with EA (3X50ml). The combined extracts were dried and evaporated and the residue was purified by chromatography on alumina using ER as eluent to give the title compound as an oil (0,789).

Analysis Found. CapH?BN202 requires [UJ23.2 = _ D +69.3'(CHC13) C,783; H,8.5; N,6.5. C,78,15; HAM NA.1%, 10.GB 2 129 796 A 1 INTERMEDIATE 25 [1R-[lcL(Z),2p,3p,5otll-(+)-7-[5-[[(1, 1'-Biphenyl)-4-yllmethoxy]-3hydroxy-2-(4-morpholinyl)cyclpentyll-4- heptenamide A solution of Dibal in hexane (1 M, 4.2mi) was added over 5 min to a cooled (01, stirred solution of 2,6-di-tert-butyi-4-m ethyl phenol (1.85g) in dry toluene (20mi) under nitrogen. After 1 h the solution was 5 cooled to -70'and a solution of Intermediate 19e (0.2g) in toluene (5mi) was added, the mixture was stirred at -70'for 1 h then kept at -20'for 18h. 2N hydrochloric acid (20mi) was added and the mixture allowed to warm to ambient temperature over 1 h. 2N Na2C03 Solution (20mi) was added and the mixture was extracted with EA (3x40mi). The combined extracts were dried and evaporated and the residue was purified by chromatography using 7:3 ER-methanol as eluent to give the title compound as a solid (0.1 5g), m.p. 93-94.50.10 [OC122 5 = D ' +61.6'(CI-IC13) EXAMPLE 1 [1R-[1a(Z),2P,3p,5a]]-(+)-7-[5-[[(1, 1'-Biphenyl)-4-yljmethoxy]-3-hydroxy2-(1-piperidinyl)cyclopentyll-4- 15 heptenoic acid, hydrochloride Methoda) Dibal (1 M in hexane, 5.5mi) was added dropwise at 0-20 to a stirred solution of 2,6-di-t-butyi-4- methyl phenol (2.9g) in CH2C12 (13mi). The solution was stirred at -5 to 0'for 1 hand then cooled to 200. A 20 solution of Intermediate 19a (1.3g) in CH2C12 (13mi) was added at -18 to 200. The mixture was stirred at this temperature for 2.5h, 1 N hydrochloric acid (20mi) was then added dropwise, and the mixture was stirred at room temperature for 0.5h. The phases were separated and the aqueous layer was extracted with CH2C12 (10mi). The organic extracts were combined, washed with brine, dried (Na2S04) and evaporated to give a yellow gum. The product was triturated with ER to give a pale yellow powder (0.68g). Recrystallisation from EA-methanol gave the title compound m.p. 128-130'; [(X123 = D +66.Y(CHC13) T.I.c. 25:15:8:2 EA-WrOH-1-120-NH3 Rf 0.4 Methodb) A solution of Intermediate 20a (0.27g) in acetone (7mi) and 2N hydrochloric acid (4mi) was stirred at 200for 2h. Most of the acetone was removed in vacuo and the residue extracted with ER (2x15m]; discarded). The aqueous phase was extracted with CH2C12 (2x 1 5mi), dried, evaporated and the residue triturated with ER to 35 give a solid. Recrystallisation from EA-methanol gave the title compound (104mg) m.p. 125-1260.

T.I.c. Identical mixed spot with the product of Method a.

Methodc) Asoiution of Intermediate 20b (0.1429) in THF (4mi) and 2N hydrochloric acid (4mi) was kept at 20'for3h.

Most of the THF was removed in vacuo and the residue was diluted with water (2mi) and extracted with ER (4m], discarded). The aqueous layer was extracted with CH2C12 (3x6m]) and the combined extracts were dried and evaporated. The residue was triturated with ER and the resulting solid recrystallised from EA-methanol to give the title compound (0.048g) m.p. 125-127'.

T.I.c. Identical mixed spot with the product of Method a.

2 z Methodd) A solution of Intermediate 20c (0.196g) in THF (3m]) and 2N hydrochloric acid (2m[) was kept at 200 for 0.5h. 50 Most of the THFwas removed in vacuo and the residue was diluted with water (6mi) and extracted with 1:1 PE-ER (7m], discarded). The aqueous layerwas extracted with CH2C12 (4x7mi) andthe combined extracts were dried and evaporated. The residue wastriturated with ER to givethe title compound (0.163g), m.p.

128.5-129'.

T.I.c. Identical mixed spot with the product of Method a.

Method e) Intermediate 21 a was converted into the title compoundfol [owing the procedure described for Method a using toluene as solvent, m.p. 124-1280.

T.I.c. Identical mixed spot with the product of Method a.

b 11 1 GB 2 129 796 A 11 Method f) Dibal (1 M in hexane 1 Omi) was added dropwise at O'to a stirred solution of 2,6-di-t-butyi-4-methyl phenol (4.4g) in toluene (1 5mi). The solution was stirred at O'for 1 h then cooled to -60'. A solution of Intermediate 21 b (0.7g) in toluene (5m]) was added and stirring continued for 0.5h at -60' and 2h at -10'. 2N hydrochloric 5 acid (2mi) was added followed by (after 5min) pH 6 phosphate buffer (80mi). The mixture was extracted with CH2C12 (3x50mi) and the combined extracts were dried and evaporated. The phenolic impurities were removed by chromatography using 9:1 EA-methanol as eluent and the residue- in acetone (3m1) and 5N hydrochloric acid (2m]) was kept at ambient temperature for 24h. The acetone was removed in vacuo and the residue was washed with CH2C12 (3 X 10m I) and the combined extracts were dried and evaporated. The 10 residue was triturated with ER to give the title compound (0.074g), m.p. 123-126'.

T.I.c. Identical mixed spot with the product of Method a.

Methodg) Intermediate 19b was converted into the title compound following the procedure described for Method f, 15 m.p. 124.5-127.5.

T.I.c. Identical mixed spot with the product of Method a.

Methodh) Intermediate 19c was converted into the title compound following the procedure described for Method a using toluene as solvent, m.p. 122-124'.

T.I.c. Identical mixed spot with the product of Method a.

Methodi) Mercuric trifluoroacetate (0.28g) in water (0.75mi) was added to a stirred solution of Intermediate 8 (0.19) in CH3Cl\1 (3m]). After 3h hydrogen sulphide was passed through the solution until no further precipitate was formed. The solids were removed by filtration ('Hyflo') and the filtrate was evaporated in vacuo. 0.5N Hydrochloric acid (30mi) was added to the residue and the solution was extracted with CH2C12 (3x15mi). The 30 combined extracts were dried and evaporated and the residue was triturated with ER to give a solid which was recrystallised from EA-methanol to give the title compound (0.037g) m. p. 123-126'.

T.I.c. Identical mixed spot with the product of Method a.

Methodj A solution of Intermediate 7 (75mg) in 2N NaOH (1 ml) and ethanol (2ml) was stirred at 20'for 4h. The mixture was adjusted to pH 1 using 5N hydrochloric acid and was extracted with CH2CI2. The combined extracts were washed with water, dried and evaporated and the residue was triturated with ER to give a solid 40 (51 mg). A portion was recrystallised from EA-methanol to give the title compound m.p. 124-126'.

T.I.c. Identical mixed spot with the product of Method a.

Methodk Intermediate 23a was converted into the title compoundfollowing the procedure described for Method j at 45 reflux, m.p. 124-12T.

T.I.c. Identical mixed spot with the product of Method a.

Methode A solution of Intermediate 24 (0.19) in 5N NaOH (5m]) and ethanol (1 Omi) was heated under reflux for 3.5h. The solution was adjusted to pH 6 using 2N hydrochloric acid, diluted with pH 6 phosphate buffer (50mi) and extracted with CH2C12 (3x50mi). The combined extracts were dried and evaporated and the residue in CH2C12 was treated with an excess of ethereal hydrogen chloride. The solvents were removed and the residue was triturated with ER to give the title compound (0.089) m.p. 116-119% T.I.c. Identical mixed spot with the product of Method a.

Methodm A mixture of Intermediate 23b (0.275g), zinc dust (2g), KH2P04 solution (4mi) and THF (20mi) was 60 vigorously stirred for 24h at ambient temperature. The mixture was filtered and the filtrate was adjusted to pH 1 using 2N hydrochloric acid. Most of the THF was removed in vacuo and the residue was extracted with CH2C12 (2x30mi). The combined extracts were dried and evaporated to give the title compound as an oil.

T.I.c. Identical mixed spot with the product of Method a.

h 12 GB 2 129 796 A 12 EXAMPLE 2 [1R-[lot(Z),2p,3p,Sctlj-(+)-7-[3-Hydroxy-5-[4'-methoxy(l, 1'-biphenyl)-4yllmethoxy]-2-(1- piperidinyl)cyclopentyll-4-heptenoic acid, hydrochloride Dibal (1 M in hexane, 11 mi) was added dropwise at -50 to a stirred solution of 2,6-di-t-buty]-4 methyl phenol (4.84g) in toluene (1 5mi). The solution was stirred at - Wfor 1 h then cooled to -65'. A solution 5 of Intermediate 19d (0.83g) in toluene (4m]) was added and the mixture stirred at -650 for 1 hand -10 'for 'I h.

The mixture was extracted with 2N hydrochloric acid (5x15mi) and the acidic extracts, along with the precipitated oil were neutralised with 5N NaOH (30m1) and pH 6.5 phosphate buffer (30mi). The filtered aqueous solution was extracted with dichloromethane (4x25mi) and the combined extracts were dried and evaporated. The residue in ER-CH2C12 was treated with an excess of ethereal hydrogen chloride and the 10 resulting solid was recrystallised from CH2C12-WrOAc to give the title compound (0.191 g) m.p. 124.5-125.5'.

I.r. (CHBr3) 3300 (br), 2800-2300,1720cm-1 [(X]21.6 = D +65.4(CI-IC13) EXAMPLE 3 [1R-flu(Z),2p,3P,5a]](+)-7-[5-[[(1, 1'-Biphenyl)-4-yllmethoxy]3-hydroxy-2-(4-morpholinyl)cyclopentyll-4heptenoic acid, hydrochloride Method a A solution of Intermediate 25 (0.125g) in ethanoi (1 5m 1) and 2N NaOH (5m[) was heated under reflux for 5h. The cooled solution was diluted with pH 6.5 phosphate buffer (75mi) and extracted with CH2C12 (3x40mi). The combined extracts were shaken thoroughly with 2N hydrochloric acid then dried and evaporated. The residue was triturated with ER to give the title compound (0.1 g), m.p. 66-67'.

[CL122 8 = D ' +57.6'(CI-IC13) T.I.c. 4:1 EA-methanol Rf 0.28 Methodb) A solution of Intermediate 20e (0.665g) in acetone (45mi) and 2N hydrochloric acid (5mi) was kept at ambient temperature for 18h. The acetone was removed in vacuo and the residue in water (75mi) was extracted with ER (2x50mi, discarded). The aqueous layer was extracted with CH2C12 (3x50mi) and the combined extracts were dried and evaporated to give an oil. Trituration with ER gave the title compound as a 35 - solid (0.4g), m.p. 66-670.

[a123.5 = D +58'(CI-IC13) T.I.c. Identical mixed spot with the product of method a.

Claims (10)

1. A process for the preparation of a compound of formula (1) OR2 (1) 45 (CH 2)2 X WCOON HO 4 v 50 z V wherein W is straight or branched C1-7 alkylene; X is cis or trans -CH=CH- or -CH2CH2_; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which 55 has 5 - 8 ring members and (a) optionally contains in the ring -0-, -S-, - S02-, or -NR' (where R' is a hydrogen atom, C1-7 alkyl or aralkyl having a C1-4 alkyl portion); andlor (b) is optionally substituted by one or more C1-4 alkyl groups; and R % (i) straight or branched C1-5 alkyl substituted by (a) phenyl [optionally substituted by C1-6 alky], C5-7 cycloaiky], phenylalkyl having a C1-3 alkyl portion, thieny], phenyl (optionally substituted by C1-4 alky], C1-4 60 alkoxy or phenyl)], (b) thienyl [optionally substituted by C1-6 alkyl, C1- 6 alkoxy, C5-7 cycloalkyl or phenyl (optionally substituted by C1-3 alkyl, C1-3 alkoxy or halogen)], or (c) naphthyl (optionally substituted by C1-4 alkyl or C1-4 alkoxy), or (ii) cinnamyi, or a physiologically acceptable salt or solvate thereof, which process comprises 13 1 GB 2 129 796 A 13 (A) hydrolysing a corresponding compound of formula (2) 1 OR2 H 4 ACH2)2XW2 0 v (2) where R2, y, X and Ware as defined above and Z is (a) -C02R1 where R' is (1) -CR 4 R5R 6 in which R 4 and R5 are each phenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy, di-(C1-4) alkylamino, nitro or halogen) and R 6 is a hydrogen atom or a substituted or unsubstituted phenyl group as definedforR 4 and R', (2) -SiR 7 R8R9 where R 7, R 8 and R9 are aryi or C1-6 alkyl, (3) -CH2CC13 (4) -CH2CH=CH2.

(5) -CH(Rlo)BCH2R" where B is -0- or -S-, and where R10 and C are H orCl4 alkyl, orwhere R10 and C together represent -(CH2)2_ or -(CH2)3-, (b) -CONR 12 where R 12 is H or C1-4 alkyl 2 (c) -CN, or (d) -C(OCH2)3CR 13 where R 13 is C1-4 alkyl; or (B) reducing and simultaneously or subsequently hydrolysing a corresponding compound of formula (3) 25 OR2 1 1 ' (C H 2)2 X W Z 1.1 0 v (3) and optionally, after the formation of the compound of formula (1), performing one or more of the following 35 conversions: (C) (i) liberating the free acid of formula (1) from a salt initially formed, (ii) converting one salt of formula (1) into another, or (iii) treating a compound of formula (1) with an acid or a base to form a salt.

2. A process as claimed in claim 1 wherein Z is a group of thetype (a) (1).

3. A process as claimed in claim 2 wherein R' is triphenyl methyl.

4. A process as claimed in claim 1 wherein R' istetrahydropyran-2-yi.

5. A process as claimed in claim 2 or claim 3 wherein the hydrolysis is effected with NaOH, KOH, hydrochloric acid, trifluoroacetic acid or acetic acid.

6. A process as claimed in any of the preceding claims wherein the compound of formula (1) produced is 45 isolated in the form of a salt.

7. A process as claimed in claim 2 or claim 3 wherein the hydrolysis is effected with hydrochloric acid and the compound of formula (1) is isolated as its hydrochloride salt.

8. A process as claimed in any of the preceding claims wherein W is CH2CH2-, X is CiS -CH=CH-, Y is morpholino or piperidino, and R 2 is benzyl in which the phenyl group is substituted by phenyl, toly] or 50 methoxyphenyl.

9. A process as claimed in claim 8 wherein the compound produced is [1R[1(X(Z),2p,3p,5ctll-(+)-7-[5[[(1,1'-biphenyi)-4-yilmethoxy]-3-hydroxy-2-(1-piperidinyi)cyclopentyll-4he ptenoic acid hydrochloride.

10. A process as claimed in claim 9 which comprises treating the triphenyimethyl ester of said compound with hydrogen chloride or hydrochloric acid.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1984.

Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.