WO1993002089A1

WO1993002089A1 - Ketophosphanate coupling procedure

Info

Publication number: WO1993002089A1
Application number: PCT/GB1992/001290
Authority: WO
Inventors: Alan Hornsby Davidson; Christopher Mark Blackwell; Christopher Norman Lewis
Original assignee: British Bio Technology Ltd
Current assignee: Vernalis R&D Ltd
Priority date: 1991-07-22
Filing date: 1992-07-15
Publication date: 1993-02-04
Anticipated expiration: 1994-01-22
Also published as: AU2312692A; GB9115773D0; ZA925525B

Abstract

Compounds of general formula (I), wherein Z is a bulky organic substituent; Y is a hydroxy, alkylsiloxy or a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or a CO2R group; X is a hydroxy, alkylsiloxy, -CN, a CO2R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; R is C1-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylC1-8 alkyl, C2-8 alkenyl or a C1-8 alkyl substituted phenyl group; may be prepared in good yield and with minimal side reactions by reacting a compound of general formula (II), wherein Z is as defined as in general formula (I), with a compound of general formula (III), wherein X and Y are as defined in general formula (I); in the presence of a weak hydroxylic base such as lithium hydroxide (but excluding strong bases such a sodium hydroxide or potassium hydroxide), or a Group (I) or Group (II) carbonate, in a substantially anhydrous solvent. The reaction is useful for the preparation of mevinic acid derivatives which are HMG-CoA reductase inhibitors and avoids the low temperatures necessary in prior art methods.

Description

Ketophosphanate coupling procedure

This invention relates primarily to novel synthetic procedures of compounds which are useful intermediates in the synthesis of a range of mevinic acids.

A number of mevinic acids have been reported to be potent inhibitors of the enzyme 3-hydroxy -3- methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia.

Thus W F Hoffman et al (J. Med. Chem., 29, 849-852 (1986)) have reported the synthesis and testing of a compound now known as simvastatin, having the structure

EP-A-0251625 (Inamine) discloses compounds of structure

where R is similar to the corresponding group in the compounds described above, R¹ is a group of formula CH₂OH, CH₂OCOR³, CO₂R⁴or CONR⁶R⁷ wherein R³, R⁴, R⁶, and R⁷ can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.

The compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations. However, a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.

Accordingly, Heathcock and Rosen disclosed in US 4,950,775 the total synthesis of compactin, which also possesses HMG-CoA reductase inhibitory activity, and which has the structure

The synthetic procedure disclosed therein involved a key step involving a Horner Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:

and a ketophosphonate reagent corresponding to the substituted ethyl tetrahydropyran moiety:

Similarly, WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids. In particular the document describes the synthesis of (1S,2S,4aR,6S,8S,8aS,4^,R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-napthalenyl) ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one which has the structure:

The synthetic procedure disclosed in WO-A-9100280 also utilised as a key step a Horner Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:

and a ketophosphonate:

Horner Wadsworth Emmons couplings have also been described in the art, a typical description being contained in Synthesis, Commun, 884, (1979) wherein simple aldehydes, such as benzaldehydes, were converted in good yield to alkenes in the presence of sodium or potassium hydroxide in a solvent such as tetrahydrofuran or dichloromethane:H2O by treatment with a reagent such as

(CH₃O)₂P(O) CN

With more complex substrates and reagents, however, lower yields were obtained.

Similarly, in both US 4,950,775 and WO-A-9100280 only moderate yields of product were obtained at this step. The reaction conditions described therein involved using lithium salts of strong bases, such as lithium hexamethyldisilazide, or lithium salts such as lithium chloride in the presence of bases of moderate strength, such as DBU, to catalyse the coupling. It was found that side reactions occurred, including beta- elimination reactions involving reagent and product, and epimerisation of the starting aldehyde. Moreover, these side products were difficult to remove, thus lowering the isolated yields still further and adversely affecting the economic advantages of the totally synthetic route referred to above.

Therefore, although the prior art and the work disclosed in US 4,950,775 and WO-A-9100280 are pioneering, there is still room for further improvement in the synthetic methodology used, net laast to enable coupling of large, bulky substrates and reagents and in particular those containing a variety of reactive centres capable of side reactions and especially those labile under basic conditions, in order to optimise yield and facilitate recovery of products.

It has now been found that other conditions and reactants may be used to expedite such couplings to prepare, inter alia intermediates of mevinic acids in high yield.

According to a first aspect of the invention there is provided a process for the preparation of a compound of general formula I

wherein Z is a bulky organic substituent;

Y is a hydroxy, alkylsiloxy, a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or CO₂R group;

X is a hydroxy, alkylsiloxy, -CN, a CO₂R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; and R is C_1-8 alkyl, C_3-8 cyclcalkyl, C_3-8 cycloalkylC_1-8 alkyl, C_2-8 alkenyl or a C_1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II

wherein Z is as defined as in general formula I, with a compound of general formula III

wherein X and Y are as defined in general formula I;

in the presence of a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.

As used herein the term "C_1-8 alkyl" refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.

As used herein the term "C_2-8 alkenyl" refers to straight chain or branched chain. hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2- butenyl and 2-methyl-2- propenyl.

As used herein the term "C2_-8 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, propynyl, butynyl and pentynyl. As used herein the term "C1_-8 alkoxy" refers to straight chain or branched chain alkoxy groups having from one to eight carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy.

As used herein the term "hydroxy C_1-8alkyl" refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group. Illustrative of such alkoxy groups are hydroxyethyl and hydroxyn-propyl.

As used herein, the term "C_3-8 cycloalkyl" refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "C_4-8 cycloalkenyl" refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds IIlustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo.

As used herein the term "substituted alkyl" refers to a straight or branched chain hydrocarbon group of one to three carbon atoms substituted with one or more aryl groups. Illustrative of such groups are benzyl and diphenyl methyl. As used herein, the term "alkylsiloxy" refers to a siloxy group substituted with from one to three alkyl groups, each alkyl group independently being straight or branched and having from one to eight carbon atoms. Illustrative of such groups are trimethylsiloxy, triisopropylsiloxy and t-butyldimethylsiloxy.

As used herein the term "suitable protecting group" refers to a group temporarily attached to a reactive centre in a multi-functional molecule. The protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites. For a good review of protecting groups, see "Protective Groups in Organic Synthesis", Greene, T W Ed., John Wiley and Sons, 1981.

Preferably, Z comprises two or more 5 or 6 membered rings either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from a C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkoxy, hydroxy C_1-8alkyl, hydroxy, halogen, OCOR or CO₂R group. Examples of Z containing two or more 5 or 6 membered saturated rings fused together include decahydronaphthalenyl, and [4,3,0] bicyclononyl.

Examples of Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, include octahydronapthalenyl, hexahydronapthalenyl, benzocyclohexyl, benzocyclopentyl, and benzocyclohexenyl. Examples of Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, and each optionally containing one or more heteroatoms include benzimidazolyl, quinolinyl and isoquinolinyl.

Examples of Z containing two or more 5 or 6 membered rings joined via a single bond, each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include cyclohexylbenzyl, biphenyl, phenylpyridyl and phenyl pyrazolyl.

Examples of Z containing two or more 5 or 6 membered rings joined via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include 2,2-diphenylvinyl.

One advantage of the invention is that the coupling reaction may be performed at a temperature between 20°C and 40°C. The reaction temperature is preferably room temperature. Clearly therefore, this is an advantage since, with the coupling reaction used previously, it was often necessary to use temperatures as low as -70°C which, of course presents great problems if the reaction is to be used on a large scale.

Furthermore, using the process of the invention, it is possible to obtain the product in yields of 80-90% whereas with previous methods, yields were, at the most, about 66% and were often a great deal lower than this. The invention represents, in this respect, a significant improvement over prior art methods. A further advantage of the invention is that base sensitive moieties of the substrate, reagent or product, or base labile protecting groups on the substrate, reagent or product, are stable under the reaction conditions.

It will be appreciated by those skilled in the art that the nature of the solvent of a given reaction is important, for example on grounds of solubility of substrate, reagents and products, or for ease of working up the reaction products. The reaction of the invention is particularly adaptable since it may be carried out in either a water miscible solvent, for preference t-butanol or isopropanol, or a water immiscible solvent, for preference diethyl ether. The solvent will be chosen according to the reactants and products in each case.

Lithium hydroxide and caesium carbonate have been found to be particularly effective bases for use in the coupling reaction. It is preferable to carry out the reaction in an aprotic solvent such as diethyl ether if lithium hydroxide is used as a base but when the base is caesium carbonate, the reaction proceeds more efficiently in a protic solvent such as t-butanol.

Although it is preferable to use previously dried solvents for the coupling reaction, the reaction itself is unaffected by small amounts of water. Thus caesium carbonate may be used without drying, and lithium hydroxide may be used as the commercially available monohydrate.

The coupling reaction may be carried out with a ratio of compound of formula III:base of from 0.9:1 to 1.5:1 and it is preferred that the ratio is 1:1. The ratio of compound of formula II: compound formula III may be from 0.5:1 to 1:1.

The reaction is especially suitable for the preparation of a compound of general formula I

wherein X and Y are as defined above and Z is a fused ring system of general formula IV

wherein

R³ represents a hydrogen atom, COC_1-8 alkyl, COC_3-8 cycloalkyl, COC_3-8 cycloalkylC_1-8 alkyl, COC_2-8 alkenyl, COC_1- ₆ alkyl substituted phenyl group, or a suitable protecting group;

R⁴ represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl group, or a C_1-5 alkyl, C_2-5 alkenyl, C_2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C_1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;

R⁵ represents a hydrogen atom or a C_1-8 alkyl group;

R⁶ represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond.

These compounds of general formula I are mevinic acid derivatives which, as has been discussed, are potent inhibitors of HMG-CoA reductase.

It is particularly preferred to use the method of the invention to prepare compounds of general formula I wherein:

Y is hydroxy or alkylsiloxy; and X is a CO₂R C_1-8 alkyl group.

Examples of compounds of general formula III are: methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate; and methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate. Compounds of general formula II which are suitable for use in the coupling reaction include:

{(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]- 6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde);

{(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};

{(1S,2S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2-methyl-8-[(2"- (S)-methyl-1"-oxobutyl)oxy]naphthalene-1-carbaldehyde};

{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a-octahydro-2,6- dimethyl-8-[(2"-(S)-methy1-1"-oxobutyl)oxy]naphthalene- 1-carbaldehyde);

{ (1S,2S,4aR,6R,8S,8aS)-6-(t-butyldiphenylsiloxy)- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-(S)-methyl-

1"-oxobutyl)oxy]-naphthalene-1-carbaldehyde);

{(1S,2S,6S,8S,8aS)-1,2,6,7,3,8a-hexahydro-2,6-dimethyl8- [(2",2"-dimethy1-1"-oxobutyl)oxy]naphthalene-1- carbaldehyde};

{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6- dimethyl- 8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalene1- carbaldehyde); or

1-benzyl-2-phenyl-4-isopropylimidazole-5-carbaldehyde.

Compounds of general formulae II and III are known in the art or can be prepared by methods analogous to those in the art.

In a second aspect of the invention there is provided a process for the preparation of a methyl (1S,2S, 4aR,6S,8S,8aS,3^,R)-7'-(1,2,4a,5,6,7,8,8a-octahydro- 2- methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop- 1-enyl]-1-naphthalenyl)-3'-trialkylsilyl- oxy-5'- oxohept-6'-enoate, the method comprising reacting a methyl (R) -3-[ (trialkylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate and either lithium hydroxide or caesium carbonate in a substantially anhydrous solvent.

In a further aspect of the invention, there is provided a process for the preparation of compounds of general formulae V and VI

wherein:

R³, R⁴, R⁵ and R⁶ are as defined in general formula IV;

R⁷ represents a hydrogen atom or a substituent R⁸ or M;

R⁸ represents a C_1-5 alkyl group, or a C_1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;

M represents a cation capable of forming a pharmaceutically acceptable salt;

Q represents C=O or CHOH; and each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; the process comprising preparing a compound of general formula I by the process of the invention and subsequently converting the compound of general formula I to a compound of general formula V or VI by any suitable method.

A suitable method for this conversion is described in WO- A-9100280.

Preferred compounds which can be made by this method are:

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8, 8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one; and

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8, 8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)- oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl)- tetrahydro-4'-hydroxy-2H-pyran-2'-one.

The following examples, which are for the purposes of illustration only, show the synthesis of a compound of general formula I from a compound of general formula II and a compound of general formula III using two alternative routes. Organic solutions were dried over anhydrous magnesium sulphate. Ether refers to diethyl ether. NMR spectra aquired at 250MHz (proton) or 62.9MHz (carbon) in deuteriochloroform unless noted otherwise. Coupling constants are given in Hertz.

Example l

Methyl (1S,2S,4aR,6S,8S,8aS,3^,R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]6- [ (E) -prop-1-enyl ] -1-naphthalenyl ) -3 ^, -t-butyldimethylsilyl-oxy-5 ' -oxohept-6 '-enoate.

USING LITHIUM HYDROXIDE

A mixture of methyl (R)-3-[(tert-butyldimethylsilyl) oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (241 mg, 0.63 mmol) and lithium hydroxide monohydrate (26.5 mg, 0.63 mmol) in anhydrous ether (3 mL) was stirred at room temperature under argon for 35 minutes. The aldehyde

{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a- octahydro-2- methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-

1-enyl]naphthalene-1-carbaldehyde) (131 mg, 0.40 mmol) in ether (3 mL) was added and the resulting solution stirred for 7 days. The solution was then diluted with more ether

(10 mL), washed with ammonium chloride solution (3 mL) and brine (2 mL). Column chromatography eluting with hexane:ethyl acetate (12:1) gave the unreacted starting aldehyde (12 mg) followed by the required enone (193 mg,

82%; 92% with respect to unrecovered aldehyde). delta H 6.77 (1H, dd, J = 17.5 and 10), 6.01 (1H, d, J = 17.5), 5.75 (1H, ddq, J = 15, 7.5 and 2.5), 5.65 (1H, dq, J = 10.5 and 2.5), 5.50 - 5.30 (2H, m), 4.95 (1H, m), 4.62 (1H, m), 3.68 (3H, s), m.83 (1H, dd, J = 17.5 and 5), 2.74 (1H, dd, J = 17.5 and 5), 2.65 - 2.2 (6H, m), 2.05 - 1.2 (10H, m), 1.14 (3H, s), 1.12 (3H, s), 0.95 (3H, d, J = 7.5), 0.88 - 0.72 (12H, m), 0.08 (3H, s), 0.03 (3H, s)

delta C 195.77 175.15, 170.05, 147.05, 134.46, 130.73, 130.54, 129.51, 121.68, 68.77, 64.55, 49.99, 46.09, 41.33, 41.23, 41.11, 41.01, 40.03, 35.70, 34.53, 34.44, 34.00, 31.56, 29.31, 24.30, 23.23, 23.05, 16.47, 15.03, 7.77, -6.13, -6.47 Using the above method with 7.0 g of aldehyde (21 mmol), 11.29 g of keto-phosphonate (6a) (29.5 mmol) and 1.24 g of lithium hydroxide gave 0.92 g of recovered aldehyde and 9.45 (76%; 88% with respect to unrecovered aldehyde) of enone.

Example 2

Methyl (1S,2S,4aR,6S,8S,8aS,3'R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]6- [(E)-prop-1-enyl]-1-naphthalenyl)-3'-triisopropyl-silyl- oxy-5'-oxohept-6'-enoate.

Using the method of Example 1 with 25 mg of aldehyde (0.075 mmol), methyl (R)-3-[triisopropyl- silyloxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate (35 mg, 0.083 mmol) and lithium hydroxide (3.5 mg, 0.083 mmol) gave a 60% yield of enone after 4 days.

Example 3

Methyl (1S,2S,4aR,6S,8S,8aS,3^,R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethγl-1"-oxobutyl)oxy]6- [(E)-prop-1-enyl]-1-naphthalenyl)-3'-t-butyldimethyl- silyl-oxy-5'-oxohept-6'-enoate

USING CAESIUM CARBONATE tert-Butanol (14 mL) was added to a mixture of methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (1.26 g, 3.30 mmol) and caesium carbonate (1.07 g, 3.28 mmol) and the resulting solution stirred at room temperature for 40 minutes under argon. A solution of the aldehyde (l.Og, 3.01mmol) in t- butanol (6 mL) was added and the reaction stirred for 4 days. The resulting dark yellow solution was diluted with ether (40 mL) and washed with ammonium chloride solution

(20 mL). The aqueous layer was extracted with more ether

(2 x 20 mL) and the combined organic layers washed with brine (2 x 15 mL), dried and evaporated to give a dark yellow solid. Chromatography on silica eluting with firstly dichloromethane gave unreacted aldehyde (220 mg), and then with hexane: ethyl acetate (4:1) gave the desired enone as a pale yellow solid (930 mg, 53%; 68% with respect to unrecovered aldehyde). Example 4

Methyl ( 3 ^,R) - (E) -7 ' - (l-benzyl-2-phenyl-4-isopropyl- imidazol-5-yl) -3 'tert-butyldimethylsilyloxy-S'-oxohepte'- enoate

A mixture of the methyl (R)-3-[(tert-butyldimethyl- silyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (369 mg; 0.97 mmol) and lithium hydroxide monohydrate (40 mg; 0.97 mmol) in ether (5 mL) was stirred under argon for 30 minutes at room temperature. A solution of 1- benzyl-2- phenyl-4-isopropylimidazole-5-carbaldehyde (184 mg; 0.60 mmol in ether (5 mL) was added and stirring continued for 5 days after which time the reaction was diluted with ether (10 mL). The organic solution was washed with ammonium chloride solution (10 mL) and brine (5 mL), dried and evaporated to an orange semi-solid. Chromatography on silica eluting with hexane-ethyl acetate (4:1) gave the product (116mg, 34%; 89% with respect to recovered aldehyde). deltah 7.55 - 7.23 (9H m), 7.1 - 7.05 (2H m), 6.27 (1H d J = 16), 5.3 (2H s), 4.55 (1H m), 3.65 (3H m), 3.27 (1H m), 2.70 (1H dd J = 15 and 6), 2.62 (1H J = 15 and 6), 2.52 (dd J = 14.7 and 5.5), 2.42 (dd J = 14.7 and 5.5), 1.41 (3H s), 1.38, (3H s), 0.81 (9H s), 0.03 (3H s), -0.03

(3H s). deltaC 195.83, 170.07, 153.61, 150.00, 135.20, 128.56, 128.09, 127.84, 127.59, 127.37, 127.28, 126.47, 124.18, 122.27, 121.04, 65.00,50.04, 47.46, 47.26, 41.11, 25.95,

24.27, 20.78, 16.46, -6.41.

From the above Examples, it can be seen that the coupling reaction of the invention can be carried out at room temperature and it is not necessary to use the extreme conditions which were essential for prior art coupling reactions.

Claims

1. A process for the preparation of a compound of general formula I

wherein

Z is a bulky organic substituent;

Y is a hydroxy, alkylsiloxy or a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or a CO₂R group;

X is a hydroxy, alkylsiloxy, -CN, a CO₂R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group;

R is C_1-8 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkylC_1-8 alkyl, C_2-8 alkenyl or a C_1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II

wherein X and Y are as defined in general formula I; in the presence of a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.

2. A process as claimed in claim 1, wherein Z comprises two or more 5 or 6 membered rings either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkoxy, hydroxy C_1-8alkyl, hydroxy, halogen, OCOR or a CO₂R group.

3. A process as claimed in claim 1 or claim 2 wherein the reaction is carried out at a temperature of from 20°C to 40°C.

4. A process as claimed in claim 3, wherein the reaction is carried out at room temperature.

5 A process as claimed in any one of claims 1 to 4 wherein the solvent is aprotic, for example diethyl ether.

6. A process as claimed in any one of claims 1 to 4 wherein the solvent is protic, for example t-butanol or isopropanol.

7. A process as claimed in any one of claims 1 to 6 wherein the base is lithium hydroxide or caesium carbonate.

8. A process as claimed in any one of claims 1 to 7 wherein the ratio of the compound of formula III:base is from 0.9:1 to 1.5:1.

9. A process as claimed in any one of claims 1 to 8 wherein the ratio of compound of formula II:compound of formula III is from 0.5:1 to 1:1.

10. A process as claimed in any one of claims 1 to 9, wherein Z is a fused ring system of general formula IV

wherein

R³ represents a hydrogen atom, COC_1-8 alkyl, COC_3-8 cycloalkyl, COC_3-8 cycloalkylC_1-8 alkyl, COC_2-8 alkenyl, COC_1- ₆ alkyl substituted phenyl group, or a a suitable protecting group;

R⁵ represents a hydrogen atom or a C_1-8 alkyl group;

11. A process as claimed in any one of claims 1 to 10 wherein:

Y is hydroxy or alkylsiloxy; and X is a CO₂ C_1-8 alkyl group.

12. A process as claimed in any preceding claim, wherein the compound of general formula III is

Methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxonexanoate; or

Methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxy- phosphonyl)-5-oxohexanoate.

13. A process as claimed in any preceding claim wherein the compound of general formula II is {(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2-methyl-8-[(2",2"-dimethy1-1"-oxobutyl)oxy]- 6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};

{(1S, 2S, 4aR, 6S, 8S, 8aS) -1,2,4a,5, 6,7,8, 8a- octahydro- 2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};

{(1S,2S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2-methyl-8-[(2"- (S)-methy1-1"-oxobutyl)oxy]naphthalene-1-carbaldehyde};

{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a-octahydro-2,6- dimethyl-8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalene- 1-carbaldehyde); {(1S,2S,4aR,6R,8S,8aS)-6-(t-butyldimethylsiloxy)-

1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-(S)-methyl- 1"-oxobutyl)oxy]-naphthalene-1-carbaldehyde);

{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl8- [(2",2"-dimethy1-1"-oxobutyl)oxy]naphthalene-1- carbaldehyde};

{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl- 8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalenel- carbaldehyde); or 1-benzyl-2-phenyl-4-isopropylimidazole-5-carbaldehyde. 13. A process for the preparation of a methyl (1S,2S,

4aR,6S,8S,8aS,3^,R)-7'-(1,2,4a,5,6,7,8,8a-octahydro- 2- methyl-8-[(2",2"-dimethy1-1"-oxobutyl)oxy]-6-[(E)-prop- 1-enyl]-1-naphthalenyl)-3'-trialkylsilyloxy-5'-oxohept- 6'-enoate, the method comprising reacting a

methyl (R)-3-[(trialkylsilyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate with {(1S,2S,4aR,6S,8S,8aS)- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl- 1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl] naphthalene-1- carbaldehyde} and either lithium hydroxide or caesium carbonate in a substantially anhydrous solvent.

14. A process for the preparation of a compound of general formula V or VI

wherein

R³, R⁴, R⁵ and R⁶ are as defined in general formula IV;

R⁷ represents a hydrogen atom or a substituent R⁸ or M; R⁸ represents a C_1-5 alkyl group, or a C_1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;

M represents a cation capable of forming a pharmaceutically acceptable salt;

Q represents C=O or CHOH; and each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; the process comprising preparing a compound of general formula I by a process as claimed in anyone of claims 1 to 11 and subsequently converting the compound of general formula I to a compound of general formula V or VI by any suitable method. 16. A process as claimed in claim 15 for the preparation of:

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one; or

(1S,2S,4aR,6S,8S,8aS,4^,R,6^,R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)- oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}- tetrahydro-4'-hydroxy-2H-pyran-2'-one.