GB2110665A

GB2110665A - Preparation of aminocyclopentanealkenoic acids

Info

Publication number: GB2110665A
Application number: GB08230768A
Authority: GB
Inventors: Ian Waterhouse; David Robert Marshall; Eric William Collington; John Wallis; Peter Hallett
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1981-10-29
Filing date: 1982-10-28
Publication date: 1983-06-22
Also published as: KR890004693B1; CA1194473A; FI823689A0; PT75761A; ES8403101A1; DK477682A; KR840001969A; ES516909A0; AU8985582A; PT75761B; GB2110665B; EP0078668A1; GR77727B; FI823689L; JPS5883686A

Description

1

GB 2 110 665 A 1

SPECIFICATION

Preparation of aminocyclopentanealkenoic acids

This invention concerns the preparation of aminocyclopentanealkenoic acids, and is particularly concerned with the preparation of compounds of the general formula (1)

(ck2)2xwcooh

(l)

wherein

X is c/'s or trans —CH=CH—;

W is straight or branched C,_7 alkylene;

Y represents a saturated heterocyclic amino group which has 5—8 ring members and (a)

1 o optionally contains in the ring —0—, —S—, —S02—, —NR4— (where R4 is a hydrogen atom, C,_7 1 o alkyl or aralkyl having a C,_4 alkyl portion); and/or (b) is optionally substituted by one or more C,_4 alkyl groups;

R2 is (i) C3_6 alkenyl, optionally substituted by phenyl (the phenyl being optionally substituted by C,_4 alkyl, C,_4 alkoxy, halogen, C5_7 cycloalkyl or phenyl (C,_4) alkyl), biphenyl (optionally substituted 15 by C,_4 alkyl, C,_4 alkoxy or halogen), or naphthyl; (ii) C,_12 alkyl; (iii) C,^ alkyl substituted by (a) phenyl 15 [optionally substituted by halogen, hydroxy, C.,_6 alkyl, C,^ alkoxy, C,_4 hydroxyalkoxy, trifluoromethyl, cyano, aryloxy (e.g. phenoxy), C5_7 cycloalkyl, aralkoxy (e.g. benzyloxy), dimethylaminomethyl,

carboxamido (—C0NH2), thiocarboxamido (—CSNH2), C,_4 alkanoyl, —NR5R6 (where Rs and R6 are the same or different and are each a hydrogen atom or C1-4 alkyl, or where —NR5R6 is a saturated 20 heterocyclic amino group as defined above for Y), C,_3 alkylthio, C,_3 alkylsulphinyl, C,_3 20

alkylsulphonyl, phenylalkyl having a C,_3 alkyl portion, aminosulphonyl, C,_3 alkanoylaminosulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by C^ alkyl or C^ alkoxy), nitro, or thienyl], (b) thienyl orfuranyl [the thienyl and furanyl groups being optionally substituted by C.,_6 alkyl, C^e alkoxy, aryl (e.g. phenyl) or phenyl (C,^) alkyl or phenyl (C,_3) alkoxy (the aryl or phenyl group in 25 each case being optionally substituted by C,_3 alkyl, C1-3 alkoxy or halogen), aryloxy (e.g. phenoxy), 25 C5_7 cycloalkyl, halogen, nitro or thienyl], (c) biphenyl (optionally substituted by phenyl or one or two C1-4 alkyl, C,_4 alkoxy or halogen substituents), or (d) naphthyl (optionally substituted by C1-4 alkyl, C,_4 alkoxy or halogen);

and the physiologically acceptable salts and the solvates (e.g. hydrates) thereof. 30 The structural formulae herein are to be understood to include the enantiomers of each of the 30 compounds concerned as well as mixtures of the enantiomers, including racemates, even though the precise structure as set out only relates to one enantiomer.

These compounds have shown endoperoxide and thromboxane antagonist activity and are therefore of interest in the treatment of asthma and cardiovascular diseases.

35 This invention provides a process for the preparation of a compound of formula (1) or a salt or 35 solvate thereof, which comprises hydrolysing an ester of formula (2)

(ch2)2xwcoor1

(2)

(a) —CR7R8R9 in which R7 and R8 are each phenyl (optionally substituted by C,_4 alkyl, C,_4

40 alkoxy, di-(C.,_4)alkylamino, nitro or halogen) and R9 is a hydrogen atom or a substituted or 40

unsubstituted phenyl group as defined for R7 and R8;

(b) —CH2BR10 where B is —0— or —S— and R10 is C1-4 alkyl;

(c) —CH2OCOR11 where R11 is C,^ alkyl or methoxy;

(d) — CH0C0CH3

I

R12

2

GB 2 110 665 A 2

where R12 is methyl or phenyl;

(e) tetrahydro-5-oxo-2-furanyl;

(f) —CH2CH2SiRj3 where R13 is C,_6 alkyl, e.g. methyl;

(g) —CHjCC^; or

5 (h) —SiR14R1sR16 where R14, R1S and R16 are aryl (e.g. phenyl) or C^g alkyl, at least one of R14, R15 5 and R16 being aryl.

R1 is preferably a group (a), for example triphenylmethyl (in which the phenyl groups are optionally substituted by methyl, methoxy or nitro) or diphenylmethyl (in which the phenyl groups are optionally substituted by halogen, methyl, methoxy or dimethylamino). More preferably, R1 is 10 triphenylmethyl. 10

The hydrolysis of the esters of formula (2) can in general be effected under neutral or mildly acidic or basic conditions, optionally in an organic or aqueous organic solvent and at any suitable temperature, conveniently —5 to 25°C, preferably at room temperatures.

Thus when R1 is a group of the type (a), (b), (c), (d), (e), (f), or (h), hydrolysis may be effected in the 15 presence of a strong acid, preferably an organic acid such as trifluoroacetic acid. 15

Suitable solvents for such hydrolyses include tetrahydrofuran, ether, aqueous ether and CH2Cl2. The reaction may be performed at room temperature.

Alternatively, esters in which R1 is a group (h) can be hydrolysed with an acid such as acetic acid in a suitable solvent (e.g. aqueous tetrahydrofuran). This reaction may be performed at room 20 temperature. 20

When R1 is a group of type (b), hydrolysis may also be effected under neutral conditions in the presence of HgCI2 (for example using aqueous CH3CN as solvent). These esters may also be hydrolysed in the presence of AgN03, for example using buffered aqueous tetrahydrofuran, dioxan or dimethoxyethane as solvent. The reaction is preferably effected at room temperature.

25 Esters in which R1 is —CH2CCI3 may be hydrolysed by treatment with zinc, for example at a pH of 25 4.2—7.2. Tetrahydrofuran, dioxan and dimethoxyethane are suitable solvents. The reaction is preferably effected at room temperature.

Esters in which R1 is a group (h) may also be hydrolysed by a quaternary ammonium fluoride (e.g. (t-But)4NF) or HF, for example using tetrahydrofuran or CH3CN as the reaction solvent. This reaction 30 may be performed at room temperature. 30

Esters in which R1 is a group of the type (c), (d) or (e) may also be hydrolysed under basic conditions, for example in the presence of an inorganic base such as Na2HP04. The solvent may for example be an aqueous alcohol (e.g. methanol) and the reaction may be performed at room temperature.

35 The acid of formula (1) produced is conveniently isolated in the form of a salt, for example a salt 35 with an organic base, such as piperidine. If desired, the free acid may be liberated from the salt, and converted into another salt if required. The salt initially isolated may also be converted directly into another salt without liberation of the acid, by exchange of cation.

Thus, salts of inorganic bases may be prepared by adding the base to a solution of the acid of 40 formula (1) in an aqueous organic solvent. Certain salts may also be prepared by exchange of cation; 40 for example, calcium salt may be prepared by addition of a calcium salt (e.g. the chloride or acetate) to a solution of a salt of a compound of formula (1), e.g. an amine or alkali metal salt.

In a further aspect of the invention the esters of formula (2) are prepared by oxidising a corresponding hydroxy compound of formula (3)

45

(CH2)2X;''COOr1 45

(3)

(other than compounds in which Y is in the a-configuration and the ring hydroxy group is in the /}-configuration).

Suitable methods of oxidation include using a Crvi oxidising reagent in a suitable solvent, e.g.

chromic acid in acetone (e.g. Jones reagent, preferably used in the presence of a diatomaceous silica 50 such as Celite) or Cr03 in pyridine. These reagents are for example used at temperatures of —20°C to 50 room temperature.

Other important methods include using an activated sulphur reagent, e.g. (i) N-chlorosuccinimide-dimethylsulphide complex in a suitable solvent (e.g. toluene or dichloromethane) at temperatures of for example —25 to 25°C, preferably at 0—5°, (ii) a dialkyl sulphoxide (e.g. 55 dimethylsulphoxide) activated by a suitable electrophilic reagent (such as oxalyl chloride, acetyl 55

3

GB 2 110 665 A 3

bromide or thionyi chloride) in a suitable solvent (e.g. toluene or dichloromethane), e.g. at —70 to —20°C; dicyclohexylcarbodiimide can also be used as the electrophilic reagent (preferably in the presence of CF3C00H or its pyridinium salt) at for example —10°C to room temperature, using the same solvents, or (iii) pyridine-S03 complex in dimethylsulphoxide, preferably at 0°C to room 5 temperature.

The choice of oxidation method will depend on the nature of R1.

When Y is in the a-configuration conditions should be chosen to effect epimerisation after oxidation, for example by using a Crvl oxidising agent.

Any hydroxy or amino group present in the starting material and required in the end product 10 should be suitable protected in this reaction.

The compounds of formula (3) may be prepared by esterification of the corresponding carboxylic acid, i.e. a compound of formula (3) in which R1 represents a hydrogen atom. Conventional esterification methods may be used.

For example, compounds of formula (3) in which R1 is a group of the type (f) or (g) may be 15 prepared by treating a reactive derivative of the corresponding carboxylic acid with an appropriate alcohol R1OH. The reactions may for example be carried out at —10°C to room temperature using a solvent such as acetone.

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 at 20 —12°C.

The chloroformate may for example be a C,^ alkyl (e.g. iso-butyl), aryl (e.g. phenyl) or aralkyl (e.g. benzyl) chloroformate.

Again for example, compounds of formula (3) in which R1 is a group of the type (a), (b), (c), (d), (e), or (h) may be prepared by reacting the corresponding carboxylic acid with an appropriate halide R17-25 Hal, where Hal represents halogen and R17 is as just defined for R1. The reaction is carried out in the presence of a suitable base, e.g. potassium t-butoxide or a sterically hindered amine such as triethylamine, N,N-diisopropylethylamine, or dicyclohexylamine in a suitable solvent (such as acetonitrile, dimethylsulphoxide, dimethylformamide orCH2CI2) for example at a temperature from 0°C to room temperature.

30 In another example, compounds of formula (3) in which R1 is a group of the type (a) where R9 is a hydrogen atom may be prepared by reacting the corresponding carboxylic acid with an appropriate diphenyldiazomethane in a solvent such as benzene at e.g. room temperature.

The parent carboxylic acids required for the preparation of the esters of formula (3) may be prepared as described in British Patent Specification 2075503A.

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

The alkyl groups referred to above in the definition of the compounds of formula (1) may be straight or branched.

W may for example contain 1 —5 carbon atoms in a straight or branched chain, and is preferably 40 —CH2CH2—.

The compounds of formula (1) are capable of salt formation with bases and the compounds are preferably used in the form of such salts. Examples of suitable salts are alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium, substituted ammonium (e.g. tromethamine ordimethylamino-ethanol), piperazine, N,N-dimethylpiperazine, morpholine, piperidine 45 and tertiary amino (e.g. triethylamine) salts. Inorganic salts are preferred.

X is preferably a cis —CH=CH— group.

The heterocyclic amino group Y may for example have a 5, 6 or 7-membered ring, e.g.

pyrrolidino, piperidino, morpholino, piperazino, thiomorpholino, 1,1 -dioxothiomorpholino, homomorpholino and hexamethyleneimino. Examples of the optional substituents which may be 50 present on a second nitrogen atom in the ring are methyl, ethyl and benzyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl or ethyl. Y is preferably piperidino, morpholino, homomorpholino, thiomorpholino or 1,1 -dioxothiomorpholino, and compounds in which Y is a morpholino or piperidino group are particularly preferred.

The amino group Y enables the compounds to form salts with organic acids, e.g. maleates. 55 R2 may for example be C5_10 alkyl (e.g. pentyl or decyl); C3_s alkenyl (e.g. allyl, optionally substituted by phenyl); or C^ alkyl (e.g. methyl or propyl) substituted by phenyl (optionally substituted by a C,_4 alkyl (e.g. tert. butyl), C5_7 cycloalkyl (e.g. cyclohexyl), C,_3 alkylthio (e.g. methylthio), phenyl (C.|_3) alkyl (e.g. benzyl) or thienyl], furanyl or thienyl (optionally substituted by a phenyl group),

biphenyl [optionally substituted by C,_3 alkyl (e.g. methyl), C,_3 alkoxy (e.g. methoxy), halogen (e.g. 60 chlorine) or phenyl], or naphthyl.

R2 is preferably a phenylalkyl group in which the alkyl portion contains 1—3 carbon atoms and the phenyl is substituted with one of the following groups: C,_3 alkylthio, thienyl or phenyl optionally substituted by C,_3 alkyl, C,_3 alkoxy, halogen or phenyl; or is thienylalkyl in which the alkyl portion contains 1—3 carbon atoms and the thienyl group is substituted by a phenyl group; or cinnamyl. 65 Particularly preferred R2 groups are phenylalkyl groups in which the alkyl portion is a C,_3

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65

4

GB 2 110 665 A 4

alkylene chain and the phenyl group carries a phenyl substituent, preferably in the para-position (which phenyl substituent is optionally substituted by a C,_3 alkyl, C^ alkoxy or halogen, this additional substituent preferably being in the meta or more particularly the para-position); or thienylmethyl group (particularly a 4-thienylmethyl group) substituted by a phenyl group, which substituent is preferably in 5 the 2-position; or cinnamyl.

Especially important R2 groups are benzyl groups substituted (preferably in the para-position) by phenyl, 4-methoxyphenyl or 4-methylphenyl.

A particularly preferred group of compounds has the formula (1) in which:

X is cis — CH=CH—,

10 Wis—CH2CH2—

Y is morpholino or piperidino, and

R2 is phenyl (C,_3) alkyl in which the phenyl group is substituted by phenyl (which phenyl substituent is optionally substituted by C,_3 alkyl, C,_3 alkoxy or halogen; phenylthienylmethyl; or cinnamyl,

15 and the physiologically acceptable salts and solvates (e.g. hydrates) thereof.

Particularly important compounds in this latter group are those in which Y is morpholino and R2 is 1,1 '-biphenylmethyl; 1,1 '-biphenylmethyl substituted in the para-position by methyl, methoxy or chloro or in the meta-position by methoxy; 1,1 '-biphenylpropyl; 2-phenyl-thien-4-yl-methyl; or cinnamyl; and those in which Y is piperidino and R2 is 1,1 '-biphenylmethyl or 4'-methoxy-1 -1 '-20 biphenylmethyl. Especially important are:

t1cK(Z),2/5,5a;]-(±)-7-[5[[(1,1,-biphenyl)-4-yl]methoxyl]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid; and

[1 R-[1 a:(Z),2/3,5a:]]-(—)-7-[5-[[(1,1 '-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid; and the hydrates and salts thereof, particularly the calcium, 25 piperidine, piperazine and N,N-dimethylpiperazine salts. The calcium salts are particularly important.

In general, compounds of formula (1) in which the carbon atom carrying the —(CH2)2XWC00H group is in the R-configuration (and mixtures containing this isomer) are preferred.

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

30 TLC—thin layer chromatography using Si02; PE—petroleum ether (boiling at 40—60°); THF— tetrahydrofuran; EA—ethyl acetate; HOAc—acetic acid; DMSO—dimethylsulphoxide; DMF— dimethylformamide. Chromatography was carried out using silica gel unless otherwise stated. 'Dried' refers to drying with MgS04. 'Hyflo' is a filtration aid.

The proportion of the following intermediates is described in British Patent Specification 35 2075503A

Intermediate 1

[1 tt(Z),2/53a,5a;]-(+)-7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid.

Intermediate 2

40 [1 R-[1 ar(Z),2/5,3a:,5ci:]]-(+)-7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxyl-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid.

Intermediate 3

[l£*(Z),2/3,5ar]-(+)-7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]]-4-

heptenoic acid.

45 Intermediate 4

[1R-[1a;(Z),2/5,5a:]]-(—)-7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid.

Intermediate 5

[1 a(Z),2/},5ar]-{±)-Triphenylmethyl-7-[5-[[(1 ,1 '-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-50 oxocyclopentyl]-4-heptenoate

Triphenylmethyl chloride (1.315 g) was added at 2° to a solution of intermediate 3 (1.5 g) and triethylamine (0.88 ml) in CH2CI2 (9 ml). After 1 h at 2—4° the mixture was diluted with pH 6 phosphate buffer (75 ml) and ether (75 ml). The ether layer was washed with water (2x25 ml), dried and evaporated. The residue was purified by chromatography using ether as eluent to give the title 55 compound as a foam (1.843 g).

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Analysis Found: C48H4gN05 required:

C,80.2;H,6.9;N,2.1; C,80.1;H,6.9;N,1.95%

5

GB 2 110 665 A 5

Intermediate 6

[1 R-[1 a{Z),2[5,5a]]-[~)-Triphenylmethyl-7-[5-[[(1,1 f-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoate

To a cooled (5—10°) stirred solution of Intermediate 2 methane suiphonate (1 g) and 5 triphenylmethyl chloride (0.6 g) in CH2CI2 (5 ml) was added triethylamine (0.6 ml). The mixture was stirred at less than 10° for 0.5 h when more triethylamine (1.7 ml) was added followed by a solution of pyridine—sulphur trioxide complex (1.1 g) in DMSO (5 ml). The cooling bath was removed and the mixture was stirred at ambient temperature for 1.5 h. Water (30 ml) was added and the mixture was extracted with ether (2x20 ml). The combined extracts were washed with water (15 ml), 1M citric acid 10 (8 ml) and water (10 ml), dried and evaporated. The residue was purified by chromatography using 2:1 ether -PE as eluent to give the title compound as a foam (0.75 g).

Analysis Found: C,80.0; H,6.7; N,1.8;

C48H49N05 requires: C,80.1; H,6.9; N,1.95%

[a]£2= —7.3° (CHCI3)

15 Intermediate 7

[1 a:(Z),2/J,5ar]-(±)-Diphenylmethyl 7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoate

A solution of Intermediate 3 (0.5 g) and diphenyldiazomethane (0.6 g) in benzene (15 ml) was stirred at ambient temperature for 4 h. The solvent was removed in vacuo and the residue was purified 20 by chromatography using ether as eluent to give the title compound as an oil (0.484 g).

Analysis Found: C,78.3; H,7.0; N,2.15;

C42H4SN05 requires: C,78.35; H,7.05; N,2.1 %

Intermediate 8

[1 R-[1 a(Z),2/5,5a]]-(—)-(Acetyloxy)methyl 7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxy]-2-(4-25 morpho(inyl)-3-oxocycfopentyl]-4-heptenoate

A solution of Intermediate 4 (0.436 g) in acetone (6 ml) containing triethylamine (0.3 ml) and bromomethylacetate (0.3 g) was stirred at 20° for 2 h. The mixture was poured into pH 6.5 phosphate buffer (50 ml) and extracted with ether (3x50 ml). The combined extracts were dried and evaporated to give an oil. Purification by chromatography using ether as eluent gave the title compound as an oil 30 (0.351 g).

Analysis Found: C,69.8; H,7.3; N,2.4;

C32H39N07 requires: C,69.9; H,7.15; N,2.55%

[or]g1-5=-8.8° (CHCI3)

Intermediate 9

35 a) [1a:(Z),2/5,5a:]-(±)-2,2,2-Trichloroethyl 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoate

Iso-butyl chloroformate (0.68 ml) was added to a cooled (—12°) stirred solution of Intermediate 3 (0.8 g) and triethylamine (0.92 ml) in acetone (32 ml) under nitrogen. After 0.5 h 2,2,2-trichloroethanol (0.76 ml) was added and 0.5 h later the mixture was allowed to warm to 0°. After 3.5 h 40 the mixture was diluted with pH 6.5 phosphate buffer (60 ml) and extracted with ether (3x65 ml). The combined extracts were dried and evaporated and the residue was purified initially by chromatography using 1:1 ether—PE as eluent then by trituration with ether to give the title compound as a solid (0.22 g) m.p. 86.5—88°.

b) [1a(Z),2/3,5a]-(±)~(2-TrimethylsiIylethyl) 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-45 morpholinyl)-3-oxocyclopentyi]-4-heptenoate m.p. 43.5—45° from Intermediate 3 and trimethylsilylethanol. Purification by chromatography using 1:2 ether—PE as eluent.

Intermediate 10

[1 R-[1 a(Z),2/5,3o:,5a]]-(+)-Methoxymethyl 7-[5-[[(1,1 '-Biphenyl)-4-yl]-methoxy]-3-hydroxy-2-50 (4-morpholinyl)-cyclopentyl]-4-heptenoate

Chloromethylmethyl ether (0.16 ml) was added to a stirred solution of Intermediate 2 (0.98 g) and dicyclohexylamine (0.44 ml) in DMF (10 ml). After 15 min the mixture was diluted with pH 6 phosphate buffer (50 ml) and extracted with EA (3x50 ml). The combined extracts were washed with water (50 ml), dried and evaporated and the residue was purified by chromatography eluting with 9:1 55 EA-methanol to give the title compound as an oil (0.8 g).

Analysis Found: C,70.55; H,7.9; N,3.1;

C31H41N06 requires: C,71.1; H,7.9; N,2.7%

[ojd5'5= +61.0° (CHCI3)

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GB 2 110 665 A 6

Intermediate 11

[1R-I1 a[Z),2[i.5a]]-[—)-Methoxymethyl 7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl}-3-oxocyciopentyl]-4-heptenoate

Pyridine-sulphurtrioxide complex (0.64 g) in DMSO (5 ml) was added to a cold (0°), stirred 5 solution of Intermediate 10 (0.53 g) and triethylamine (1.1 ml) in CH2CI2 (3 ml). The mixture was allowed to attain ambient temperature over 3 h and then poured into pH 6 phosphate buffer (50 ml) and extracted with EA (3x30 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 17:3 EA—PE (b.p. 60—80°) to give the title compound as a solid (0.34 g) m.p. 47.5—48.5°.

10 [a]g6=-7.45°(CHCI3)

Example 1

[(1 a(Z),2/3,5ai]-(±)-7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, compound with piperidine (1:1)

Method a)

15 To a cooled (ice/water) stirred suspension of Intermediate 1 (60 g) and triphenylmethyl chloride (35.4 g) in CH2CI2 (240 ml) was added triethylamine (36.5 ml).-This mixture was stirred at less than 10° for 0.5 h when more triethylamine (98 ml) was added, followed by a solution of pyridine-sulphur trioxide (66.5 g) in DMSO (240 ml). The coolant was removed and the temperature of the mixture allowed to rise to 210 over 1.75 h. Water (600 ml) was added and the mixture extracted with ether 20 (1 x420 ml, 1 x300 ml). The combined extracts were washed with water (600 ml), 1M citric acid solution (480 ml) and water (600 ml), and then treated with trifluoroacetic acid (60 ml) at 20° for 20 min. The solution was carefully neutralised with 8% NaHC03 solution (830 ml) and the layers separated. The ethereal phase was washed with 20% brine (600 ml), dried (Na2S04), made up to a total volume of 1450 ml (24 vol) with more ether and stirred at 20° during the addition of piperidine 25 (9.36 g) in ether (50 ml). The mixture was stored at 5° overnight and then filtered, washed with ether (3x180 ml) and dried (3 h/1 mmHg, 21 °) to give the title compound (40.9 g), m.p. 101—104°.T.L.C. Si02 CH2CI2-Me0H-H0Ac-H20 (95:4:0.5:0.5) Rf 0.31

Method (b)

A solution of Intermediate 5 (0.512 g) in ether (8 ml) was stirred with trifluoroacetic acid (0.7 ml) 30 at 20° for 0.5 h. Ether (25 ml) was added and the mixture poured into 15% aqueous pH 6 phosphate buffer (30 ml). The layers were separated and the ethereal phase washed with brine (20 ml), dried and evaporated. The residue in ether (10 ml) was treated with piperidine (0.068 g) at 20° for 2 h. The resultant solid was filtered off, washed with ether (3x4 ml) and dried to give the title compound (0.328 g), m.p. 103—106°.

35 Method c)

Trifluoroacetic acid (3 ml) was added dropwise to a cooled (0°) stirred solution of Intermediate 7 (0.3 g) in 1:1 CH2CI2-ether (3 ml). After 15 min the cooling bath was removed and the mixture stirred at ambient temperature for 2.25 h. The mixture was diluted with pH 6 phosphate buffer (250 ml) and extracted with ether (3x30 ml). The combined extracts were washed with brine (20 ml), dried and 40 evaporated. A solution of the residue in ether (15 ml) was treated with piperidine (0.046 g) at 20° for 1.5 h. The resultant solid was filtered off, washed with ether (2x10 ml) and dried to give the title compound (0.11 g) m.p. 95.5—99°.

Method d)

A mixture of Intermediate 9a (28 mg) and activated zinc dust (ca. 0.5 g) in THF (4 ml) and pH 45 6.35 phosphate buffer (0.8 ml) was rapidly stirred at ambient temperature for 3 h. The mixture was diluted with pH 6.35 buffer (20 ml) and extracted wtih ether (3x20 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ether as eluent. The oil in ether (1 ml) was treated with an excess of piperidine and stored at 4° for 19 h. The precipitate was filtered off, dried and evaporated to give the title compound as a solid (9 mg) m.p. 97.5—99°.

50 Method e)

A solution of Intermediate 9b (40 mg) in trifluoroacetic acid (0.8 ml) was kept at 20° for 10 min then poured into pH 6.5 phosphate buffer (50 ml) and extracted with EA (2x50 ml). The combined extracts were washed with pH 6.5 phosphate buffer (2x40 ml), dried and evaporated and the residue was purified by chromatography using ether as eluent. The residue in ether was treated with an excess 55 of piperidine to give the title compound as a solid (4 mg) m.p. 94—96.5°.

Example 2

[1 R-[1 a(Z),2/3,5a]]-(—)-7-[5-[[(1,1 '-Biphenyl-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, compound with piperidine (1:1)

Method a)

60 A solution of Intermediate 6 (0.7 g) in 1:1 CH2CI2-ether (20 ml) containing trifluoroacetic acid

5

10

15

20

25

30

35

40

45

50

55

60

7

GB 2 110 665 A 7

(0.75 ml) was stirred at 10° for 1.5 h. The mixture was diluted with pH 6 phosphate buffer (75 ml) and extracted with ether (2x30 ml). The combined extracts were washed with brine (20 ml), dried and evaporated. The residue in ether (15 ml) was treated with piperidine (100 mg) at ambient temperature for 1 h. The resultant solid was filtered off, washed with ether (2x10 ml) and dried to give the title 5 compound (0.36 g) m.p. 97—101.5° 5

Analysis Found: C,72.4; H,8.4; N,4.9;

C29H35N05. CjH^N required: C,72.6; H,8.2; N,4.9%

[o:]d4=—10.8° (CHCI3)

Method b)

10 A solution of Intermediate 8 (50 mg) in methanol (6 ml) was treated with 0.5 M Na2HP04 (1.5 ml) 10 and stirred at 20° for 30 h. The mixture was concentrated in vacuo at 20°, diluted with pH 6.5 phosphate buffer (30 ml) and extracted with EA (4x20 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ether as eluent to give an oil. The oil in ether (0.5 ml) was treated with piperidine (10 mg) and cooled to 0° for 16 h. The precipitate was 15 filtered off, washed with ether (2x2 ml) and dried to give the title compound (11 mg) m.p. 101— 15

102.5°.

Method c)

Trifluoroacetic acid (3 ml) was added dropwise to a cooled (0°) stirred solution of Intermediate 11a (0.5 g) in 1:1 CH2CI2-ether (3 ml). The cooling bath was removed and the mixture allowed to warm 20 to ambient temperature over 1 h. The mixture was neutralised with 8% NaHC03 solution, poured into 20 pH 6 phosphate buffer (50 ml) and extracted with ether (4x50 ml). The combined extracts were dried and evaporated and the residue in ether (5 ml) was treated with piperidine (135 mg). The precipitated solid was filtered off, washed with ether and dried to give the title compound (0.23 g), m.p. 93—99°.

Example 3

25 [1 a(Z),2/},5a]-(±)-7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4- 25 heptenoic acid

A suspension of the product of Example 1 (2 g) in water (50 ml) and pH 6 phosphate buffer (100 ml) was extracted with ether (4x50 ml). The combined extracts were dried and evaporated to give a solid (1.69 g). A portion was crystallised from ether-isopentane to give the title compound m.p. 99— 30 100°. 30

Claims

Claims

1. A process for the preparation of a compound of formula (1)

„ (CK2)2XWCOOH

(1)

wherein

35 X is cis or trans—CH=CH—; 35

W is straight or branched C,_7 alkylene;

Y represents a saturated heterocyclic amino group which has 5—8 ring members and (a)

optionally contains in the ring —0—, —S—, —S02—, —NR4 (where R4 is a hydrogen atom, C,_7 alkyl or aralkyl having a C,_4 alkyl portion); and/or (b) is optionally substituted by one or more C1-4 alkyl 40 groups; 40

R2 is (i) C3_6 alkenyl, optionally substituted by phenyl (the phenyl being optionally substituted by C,_4 alkyl, C,_4 alkoxy, halogen, C5_7 cycloalkyl or phenyl (C,_4) alkyl), biphenyl (optionally substituted by C^,, alkyl, C,_4 alkoxy or halogen), or naphthyl; (ii) C.,_12 alkyl; (iii) C,_5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy C^g alkyl, C,_6 alkoxy, C,_4 hydroxyalkoxy, trifluoromethyl, 45 cyano, aryloxy (e.g. phenoxy), C5_7 cycloalkyl, aralkoxy (e.g. benzyloxy), dimethylaminomethyl, 45

carboxamido (—C0NH2), thiocarboxamido (—CSNH2), C,_4 alkanoyl, —NR5Ra (where Rs and R6 are the same or different and are each a hydrogen atom or C,_4 alkyl, or where —NRSR6 is a saturated heterocyclic amino group as defined above for Y), C,_3 alkylthio, C,_3 alkylsulphinyl, C,^

alkylsulphonyl, phenylalkyl having a C,^ alkyl portion, aminosulphonyl, C,_3 alkanoylaminosulphonyl, 50 phenylsulphonyl (the phenyl portion being optionally substituted by C,_3 alkyl or C,_3 alkoxy), nitro, or 50 thienyl], (b) thienyl orfuranyl [the thienyl and furanyl groups being optionally substituted by C,^ alkyl.

8

GB 2 110 665 A 8

C^e alkoxy, aryl (e.g. phenyl) or phenyl (C^) alkyl or phenyl (C^J-alkoxy (the aryl or phenyl group in each case being optionally substituted by C,_3 alkyl, alkoxy or halogen), aryloxy (e.g. phenoxy), C5_7 cycloalkyl, halogen, nitro or thienyl], (c) biphenyl (optionally substituted by phenyl or one or two C,_4 alkyl, C1—4 alkoxy or halogen substituents), or (d) naphthyl (optionally substituted by C,_4 alkyl, C,_4 alkoxy or halogen);

and the physiologically acceptable salts and the solvates (e.g. hydrates) thereof, which process comprises hydrolysing an ester of formula (2)

(CH2)2XKCOOR1

(2)

in which R1 is:

10 (a) —CR7R8R9 in which R7 and R8 are each phenyl (optionally substituted by C1-4 alkyl, C,_4 1 o alkoxy, dMC^Jalkylamino, nitro or halogen) and R9 is a hydrogen atom or a substituted or unsubstituted phenyl group as defined for R7 and R8;

(b)—CH2BR10where Bis—0—or—S—and R10isC,_4alkyl;

(c) —CHZ0C0R11 where R11 is C,_4 alkyl or methoxy;

15 (d) —CHOCOCHg 15

I

R12

where R12 is methyl or phenyl;

(e) tetrahydro-5-oxo-2-furanyl;

(f) —CH2CH2SiR33 where R13 is C^g alkyl, e.g. methyl;

(g) —CH2CCI3; or

20 (h) —SiR14R15R18 where R14, R15 and R16 are aryl (e.g. phenyl) or C.,_6 alkyl, at least one of R14, R15 20 and R16 being aryl,

and optionally thereafter (where the initial product is in the form of a salt) liberating the free acid from the salt and/or converting the salt into another salt, or (where the initial product is an acid)

treating the acid with a base to form a salt.

25 2. A process as claimed in claim 1 in which R1 is a group of type (a). 25

3. A process as claimed in claim 1 in which R1 is triphenylmethyl.

4. A process as claimed in claim 2 or claim 3 which is effected in the presence of an organic acid.

5. A process as claimed in claim 2 or claim 3 which is effected in the presence of trifluoroacetic acid.

30 6. A process as claimed in any one of claims 1 to 5 which includes the step of preparing the 30

compound of formula (2) by oxidising a corresponding hydroxy compound of formula (3)

(CH2)2XvJCOOR1

(3)

(other than a compound in which Y is in the ar-position and the ring hydroxy group is in the /5-position).

7. A process as claimed in any one of the preceding claims in which:

35 W is C^g alkylene, 35

X is cis —CH=CH—,

Y is piperidino, morpholino, homomorpholino, thiomorpholino or 1,1-dioxothiomorpholino, and R2 is a phenylalkyl group in which the alkyl portion contains 1—3 carbon atoms and the phenyl is substituted with one of the following groups: C,_3 alkylthio, thienyl or phenyl optionally substituted by 40 C,_3 alkyl, C.,_3 alkoxy, halogen or phenyl; or is thienylalkyl in which the alkyl portion contains 1—3 40 carbon atoms and the thienyl group is substituted by a phenyl group; or cinnamyl.

8. A process as claimed in any one of the preceding claims in which:

X is cis —CH=CH—,

Wis—CH2CH2—

45 Y is morpholino or piperidino, and 45

9

GB 2 110 665 A 9

R2 is phenyl (C,_3) alkyl in which the phenyl group is substituted by phenyl (which phenyl substituent is optionally substituted by C,_3 alkyl, C,_3 alkoxy or halogen); phenylthienylmethyl; or cinnamyl.

9. A process as claimed in any one of the preceding claims in which the compound produced is

5 [1 a(Z),2/5,5a:}-(±)-7-[5-[[1,1 '-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4- 5

heptenoic acid or a salt or hydrate thereof.

10. A process as claimed in any one of claims 1 to 8 in which the compound produced is [1R-[1 a(Z),2j8,5a:]]-(—)-7-[5-[[(1,1'-biphenyl-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid or a salt or hydrate thereof.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained