This invention relates to a chemical process and particularly to a chemical process for making vascular damaging agents. Such vascular damaging agents are useful, for example, for the treatment of diseases involving angiogenesis.

The use of colchinol derivatives for the preparation of compositions for the treatment of diseases involving angiogenesis has been described in Patent Application WO 99/62506, WO 00/40529 and WO 02/04434. The compounds described therein are made by chemical modification of compounds whose basic carbon framework may be derived from the natural products such as colchicine (I). For example, Patent Application WO 99/62506 describes inter alia compounds of the formula (A), which, may in general be made in a number of steps which include a rearrangement of colchicine (I).

(I) (A)

Colchicine has been known as a starting material for chemical synthesis of colchinol derivatives for a number of years, see for example, V. Fernholz Justus, Liebigs Ann., 1950, 568, 63-72. The functional groups present in colchicine provide useful means of interconversion or introduction of functional groups, and one chiral centre is also present. Colchicine occurs naturally in the lily Gloriosa Superba, which is a native flower of

Northern India, and comprises approximately 1 to 2 wt% of the seed. The use of colchicine as a starting material on a commercial scale would result in the requirement for extensive growth of Gloriosa Superba, encur significant cost and potentially be vulnerable to unpredictable supply factors such as natural disasters. Therefore there is an on-going need for the provision of chemical processes to obtain compounds such as those of formula (A) without the use of colchicine to provide the basic carbon framework and chiral centre. Advantageously such processes would be suitable for providing all compounds of the formula (A) including those wherein the nature of a group R ₃ would not be (easily) accessible from colchicine as a starting material.

A key step in forming the basic carbon framework of compounds of the formula (A) from colchicine is the rearrangement which transforms the [6,7,7] tricyclic ring system into a [6,7,6] ring system. The most direct method of achieving this is by oxidative rearrangement, which is generally found to be low yielding. A convenient compound containing the [6,7,6] tricyclic ring system required for compounds of the formula (A), which also has the stereochemistry of colchicine is N- Acetyl colchinol, (II, R ₃ = Me). The synthesis of N-Acetyl colchinol from colchicine which has been described in the literature is low yielding (F Santavy, Collect. Czech. Chem. Commun., 1949, vol 14, 532). A more recent procedure involving formaldehyde-O-oxide has also been described, but although higher yielding, is impractical on a manufacturing scale (Dilger et al, J. Prakt. Chem., 1998, vol 340, 468-471).

(H)

A convenient possible precursor to (II) to consider as a synthetic target is the enamide (III). Such an enamide derivative can be converted into (II) by a stereoselective hydrogenation process in the presence of a suitable catalyst such as a rhodium, ruthenium or iridium complex, particularly a complex which comprises one or more chiral ligand(s).

(III) Methods of synthesising the basic carbon framework of N-acetyl colchinol have been described in the art and might be adaptable for the synthesis of (II). For example, the total synthesis of N-acetyl colchinol has been reported by Sawyer and Macdonald (Tetrahedron Letters, 1988, 29, 4839-42) where the key step is the thallium mediated cyclisation of a birayl compound as shown in Scheme 1 below.

T TII((OOCCOOCCFF ₃ )) ^{M Mee00} TFAZTFAAZBF ₃ -OEt ₂

Scheme 1

However, in our hands this procedure was found to be extremely low yielding. Also, on a commercial scale this method is undesirable because, inter alia, of the use of thallium containing reagents. The method is also disadvantageous because it gives a racemic product, and would require significant adaptation for a chiral product to be obtained. It is likely that the chiral centre would be created before the cyclisation reaction, whereas it is generally considered preferable to create chiral centres at a late stage in a total synthesis, both because of cost and preservation of chiral integrity. A different approach to a similar ring system has been described by Banwell et al (J.

Chem. Soc, Chem. Commun., 1994, 2647-49) as illustrated below in Scheme 2. However, this method proceeds in a practical yield only with an extra electron donating substituent on the phenol ring, such as the methoxy group used below, which is not suitable for compounds of the formula A as defined in WO 99/62506wherein R ₅ and R ₇ are each independently hydrogen, alkyl, halogen or nitro. The use of a lead containing catalyst is also undesirable on a commercial scale.

Scheme 2

A lengthy earlier approach to these kinds of ring systems was reported by Battersby et al (J. Chem. Soc, Perkin Trans 1, 1983, 3053-3063), in which a [6,6,6] ring system was made first, then oxidatively cleaved and re-cyclised to the [6,7,6] ring system using an intramolecular aldol condensation, as shown in Scheme 3. This method, although it might be adaptable to make compounds of the formula A, is too lengthy and inefficient to be useful on a commercial scale.

-A-

Scheme 3

Therefore there is an on-going need to provide a chemical process to provide enamide (III) which is suitable for industrial application. It will be appreciated by those skilled in the art that for a process to be suitable for industrial application it should be amenable to being used on large scale, have minimal environmental impact (for example in terms of amount of raw materials required and/or the amount of waste produced), be safe (for example use materials of low toxicity that do not produce toxic waste), and be as low in cost as possible (for example by being high yielding). The present invention provides a process for the formation of an enamide (III)

(III) wherein each R is independently selected from (l-όC)alkyl, benzyl and -C(O)(I -6C)alkyl, or two RO groups together form a (l-4C)alkylenedioxy group, comprising the steps of reductive acylation of an oxime of formula (IX)

(IX) wherein each R is independently selected from (l-6C)alkyl, benzyl and -C(O)(I -6C)alkyl, or two RO groups together form a (l-4C)alkylenedioxy group, and the hydroxy group may optionally be protected by a hydroxy protecting group; and thereafter if necessary, removal of any protecting groups.

An oxime of formula (IX) may be prepared according to the invention by the following steps: 1) formation of a keto-aldehyde compound (IV)

(IV) wherein each R is independently selected from (l-όC)alkyl, benzyl and -C(O)(I -6C)alkyl, or two RO groups together form a (l-4C)alkylenedioxy group, and wherein P is a suitable hydroxy protecting group; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group;

(V) (VI) wherein either a) R ₁ is an imine; X ₁ is halide; X ₂ is halide; R ₂ is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) R ₁ is an acetal; one OfX ₁ and X ₂ is halide and the other is -B(OH) ₂ or -B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B

atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons; R ₂ is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (VII);

3) reduction and deprotection of the enone (VII) to form a cyclic ketone (VIII);

(VIII)

4) formation of the oxime derivative (IX) of the cyclic ketone (VIII).

αx)

In one aspect of the invention, each R is independently selected from (l-όC)alkyl, benzyl and -C(O)(I -6C)alkyl. In one aspect, the R groups are all the same.

In one aspect, each R is independently selected from (l-4C)alkyl, benzyl and -C(O)(I -4C)alkyl. hi a further aspect, each R is independently selected from (l-4C)alkyl and benzyl. In a further aspect, each R is independently selected from (l-4C)alkyl. In a preferred aspect, each R group is methyl.

It will be appreciated that in some of the reactions mentioned herein it may be necessary or desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those

skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, "Protective Groups in Organic Synthesis" John Wiley and Sons, 1991)

Suitable hydroxy protecting groups include, for example a group selected from (1-

6C)alkyl, -SiL ₃ (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO ₂ (l-6C)alkyl. hi one aspect of the invention, P is selected from (l-όC)alkyl, -SiL ₃ (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO ₂ (I -6C)alkyl. In a further aspect of the invention, P is selected from (l-4C)alkyl and -SiL ₃ (wherein each group L is independently selected from (l-6C)alkyl and aryl). Suitable values for -SiL ₃ include -SiMe ₃ , -SiEt ₃ , -SiPhMe ₂ , -Si ¹ Pr ₃ , -Si ¹ BuMe ₂ and -Si ⁴ BuPh ₂ . Conveniently, P is selected from benzyl, -SiMe ₃ , -SiPhMe ₂ , and -CO ₂ Me. Preferably, P is benzyl.

Step l

The formation of a keto-aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group, is the first stage in forming the key carbon-carbon bonds of the carbon framework, in this case, the aryl-aryl bond. The methods found in the art to achieve this were found not to be suitable for these substrates as hereinbefore described. This invention provides two methods suitable for formation of keto-aldehyde (IV) as described in a) and b) hereinbelow. a) The method wherein R ₁ is an imine, X ₁ is halide, X ₂ is halide, R ₂ is an acetal or thioacetal (wherein the term 'thioacetal' refers to compounds where one or both acetal oxygens are replaced by sulfur) and the transition metal is copper is shown in detail in Scheme 4 below:

Scheme 4

It will be appreciated that although the acetal/thioacetal group shown in (XI) and (XII) above is a 5-membered ring, the process of the invention may be applied to compounds wherein the acetal/thioacetal group is a 6 membered ring or is acyclic, and wherein the carbon atoms of the acetal/thioacetal group may be substituted with one or more methyl groups. The imine represented by R ₁ is of the formula CH=NR ₃ wherein R ₃ is selected from (1- 6C)alkyl, (3-7C)cycloalkyl and (3-7C)cycloalkyl-(l-4C)alkyl. Particularly R ₃ is selected from a branched (3-6C)alkyl group and (3-7C)cycloalkyl, for example tert-butyl and cyclohexyl.

The coupling reaction shown in Scheme 4 is generally known in the art as an Ullman Coupling and has been used for the total synthesis of other natural products (Hassan et al, Chemical Reviews 2002, vol 102, 1359-1469; Fanta, Synthesis, 1974, vol 1, 9-21). Such Ullman Couplings of two different substrates ("unsymmetrical Ullman Couplings") are not generally effective under conditions as traditionally practiced for the reaction, although in some cases, having different functionality in the aromatic compounds can provide some selectivity in the reaction (Brown and Robin, Tetrahedron Lett., 1978, 2015). A selective procedure has been described in the art for coupling certain aromatic components, each of

which contain nitrogen or sulfur based functionality that can co-ordinate with copper (see for example, Ziegler et al, J. Am. Chem. Soc, 1980, 102, p790). Specifically, a lithiated aromatic compound bearing a nitrogen containing group (e.g. an imine) ortho to the lithium is reacted with copper iodide-triethyl phosphate complex to provide a copper reagent in which the copper is coordinated to the nitrogen function. The coupling partner is an aromatic iodide bearing a thioacetal ring ortho to the iodide. Co-ordination of the sulfur to the copper in the other component facilitates the selective coupling of the aromatic rings at ambient temperature.

However unsymmetrical couplings of this type: where copper bromide is employed to form the aryl copper reagent; or where the coupling partner is an aryl bromide; or where the co-ordinating group attached to the aryl halide is an acetal are not generally known in the art and previously might have been considered impractical, because of the lower reactivity of bromide in comparison to iodide. However, surprisingly, we have found that careful control of the reaction conditions enables the reaction where X ₁ and X ₂ are both bromide to work in good yield and selectivity.

The analogous reaction wherein either the imine substrate (XIII) and/or the acetal/thioacetal substrate (XIa) contained an iodide

S

(XIII) (XIa) also gave the desired product. However the use of iodides is generally undesirable in an industrial application because of the environmental impact of the iodide/iodine containing waste products. Therefore in a preferred aspect of the invention X ₁ and X ₂ are both bromide. The reaction wherein X ₁ and X ₂ are both bromide may be carried out between 20 and 50°C, preferably between 30 and 50°C, more preferably between 40 and 50°C, for example at about 45°C. The use of a lower temperature generally results in a slower reaction. The transition metal containing reagent used in this invention to achieve the coupling reaction, namely CuBr ₁ P(OEt) ₃ , may conveniently be prepared by heating triethylphosphite with a suspension of copper (I) bromide in toluene.

CuLP(OEt) ₃ may also be used as a coupling reagent.

A further variation on this method, wherein a methoxime functional group replaces the acetal/thioacetal, (XIV),

(XIV) was also found to undergo the coupling reaction with imine (X) in a similar manner. hi order to obtain the desired final product of this stage, namely the keto aldehyde (IV), a simple functional group interconversion is carried out, namely formation of the keto group from the acetal/thioacetal group as shown in Scheme 5 below.

equiv)

Scheme 5

In a particular embodiment, the ketone derivative is an acetal such as (XII) where both Y = O. The use of acetals in Ullmann couplings is novel. Conveniently, when (XII) is an acetal, conversion to the ketone and the aldol reaction to make (XII) can be combined together in the same reaction vessel and solvent, without isolation of the intermediate (FV). Use of an acetal (XII) (both Y=O) rather than a thioacetal (at least one Y = S) provides further advantages: when a thioacetal is used, the resulting sulfur containing by-products are comparatively difficult to remove and may cause difficulties (such as poisoning of transition metal catalysts) later in the process of the invention.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an imine, X ₁ is halide, X ₂ is halide, R ₂ is an acetal and the transition metal is copper.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an imine, X ₁ is bromide, X ₂ is bromide, R ₂ is an acetal and the transition metal is copper.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an imine, X ₁ is halide, X ₂ is halide, R ₂ is a thioacetal and the transition metal is copper.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an imine, X ₁ is bromide, X ₂ is bromide, R ₂ is a thioacetal and the transition metal is copper.

b) The method wherein R ₁ is an acetal; one OfX ₁ and X ₂ is halide and the other is - B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; and the transition metal is palladium is shown in detail in Scheme 6 below:

(XVII) Scheme 6

It will be appreciated that although the acetal group shown in (XVa), (XVb) and (XVII) above is a 5-membered ring, the process of the invention may be applied to compounds wherein the acetalgroup is a 6 membered ring or is acyclic, and wherein the carbon atoms of the acetal group may be substituted with one or more methyl groups.

The coupling reaction shown in Scheme 6 is generally known in the art as a Suzuki Coupling, which is generally a highly efficient method of coupling together two aryl substrates (See A. Suzuki, Handbook of Organopalladium Chemistry for Organic Synthesis, (2002), 1, 249-262. Publisher John Wiley). One substrate in a Suzuki coupling is a halide and the other substrate is a boronic acid or ester derivative thereof. A number of transition metal catalysts are known in the art to be generally useful in Suzuki couplings and for compounds of the formula (XV) an (XVI), the catalyst Pd(PPh ₃ ) ₄ was found to be effective.

The coupling reaction may be carried out using either the boronic acid derivative (XVIc) or a boronic ester for example (XVId), wherein P is a protecting group as defined herein. In a preferred aspect of the invention a boronic ester is used. In a further preferred aspect, the boronic ester is (XVId).

(XVIc) (XVI d)

In order to obtain the desired final product of this stage, namely the keto aldehyde (IV), a simple functional group interconversion is carried out, namely formation of the aldehyde group from the acetal group as shown in Scheme 7 below.

(XVII) (IV) Scheme 7

Conveniently, the keto acetal (XVII) may be converted to the keto aldehyde (IV) without isolation in the reaction mixture resulting from the Suzuki coupling reaction.

The keto aldehyde (IV) may be used in the next stage of the process of the invention without isolation. In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; one OfX ₁ and X ₂ is halide and the other is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; and the transition metal is palladium.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (TV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; X ₁ is halide and X ₂ is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; and the transition metal is palladium.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula

(V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; X ₁ is Bromide and X ₂ is -B(OH) ₂ ; R ₂ is a ketone; and the transition metal is palladium.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; X ₁ is bromide and X ₂ is B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; and the transition metal is palladium.

In a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; X ₂ is halide and X ₁ is

-B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; and the transition metal is palladium. hi a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; X ₂ is bromide and X ₁ Is -B(OH) ₂ ; R ₂ is a ketone; and the transition metal is palladium. hi a further aspect of the invention is provided a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI) ₃ followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; X ₂ is bromide and X ₁ Is -B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; and the transition metal is palladium.

Step 2

Intramolecular cyclisation of the keto-aldehyde compound (V) to form an enone (VIII) is the second stage in forming the key carbon-carbon bonds of the carbon framework and completes formation of the tricyclic ring system.

The process of the invention achieves intramolecular cyclisation by the use of an aldol condensation reaction (see for example, Comprehensive Organic Chemistry, ed. Trost and Fleming). This may be carried out under any conditions known in the art, for example those shown in Scheme 8 below.

Scheme 8

The base used may be any base known to be useful in aldol reactions, for example an aqueous base. Suitably the base is potassium carbonate. It will be appreciated by those skilled in the art that such an aldol reaction may also be carried out using acid catalysis instead of base catalysis.

A further aspect of the invention comprises conversion of the keto-aldehyde compound (IV) to the enone (VII) by an intramolecular aldol condensation reaction. A further aspect of the invention comprises conversion of the keto-aldehyde compound (IV) to the enone (VII) by an intramolecular aldol condensation reaction in the presence of aqueous potassium carbonate.

Step 3

Reduction of the enone (VII) to form a cyclic ketone (VIII) may be carried out using any suitable processes well known in the art for reduction of enones, for example by hydrogenation using a palladium catalyst such as Pd(OH) ₂ . The protecting group P may be removed by any conventional means known in the art. Conveniently, when the protecting group P is benzyl, hydro genolysis of the benzyl group may be carried out simultaneously as

shoλvn below in Scheme 9. Alternatively, when Pd/C is used as the catalyst, enone reduction occurs without hydrogenolysis of the benzyl group.

(Vila) (VIII)

Scheme 9 A further aspect of the invention comprises conversion of the enone compound (Vila) to the cyclic ketone (VIII) by simultaneous palladium catalysed hydrogenolysis.

Where P is not benzyl, the conversion of the enone (VII) to the cyclic ketone (VIII) is carried out stepwise, with removal of the protecting group P by any method known in the art for the removal of a hydroxy protecting group, suitably being carried out either before or after hydrogenation of the enone group . Step 4

The formation of the oxime derivative (IX) of the cyclic ketone (VIII) may be carried out by any process known in the art for the formation of oximes, for example by reaction with hydroxylamine hydrochloride, as shown in Scheme 10.

(VIII) (IX)

Scheme 10

A further aspect of the invention comprises conversion of the cyclic ketone compound (VIII) to the oxime (IX). Step 5 Reductive acylation of the oxime (IX) to form the enamide (III) may be carried out by processes known in the art. For example a suitable method for the reductive acylation uses iron and acetic anhydride in acetic acid as shown in Scheme 11.

(IX) (III)

Scheme 11

A further aspect of the invention comprises conversion of the oxime (IX) to the enamide (III). In an alternative embodiment of the invention, the protecting group P is not removed during step 3, but is instead removed during step 5, according to Scheme 12.

(VII) (Villa)

(III) (IXa)

Scheme 12

The protecting group P may conveniently be removed before or after the reductive acylation reaction, by any suitable process known in the art depending on the nature of P.

Those skilled in the art of organic synthesis will be able to devise a variety of routes to alternatively protected precursors described herein. For example: 2,3,4-trihydroxy benzaldehyde is readily prepared from pyrogallol (B. Clichy et al. Polish patent PL145962 (1989)); derivatisation of the of the phenol group with the desired protecting groups R, followed by bromination, as described herein for the trimethoxy compound, leads to compounds of type (V); compounds of type (VI) with protecting groups other than benzyl can be prepared by simple modification of the route described herein for the benzyl derivative.

(V)

Scheme 13

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5):

1) formation of a keto-aldehyde compound (IV) wherein each R is (l-6C)alkyl and wherein P is selected from (l-6C)alkyl, -SiL ₃ (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO ₂ (I- 6C)alkyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein either a) R ₁ is an imine; X ₁ is halide; X ₂ is halide; R ₂ is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) Ri is an acetal; one OfX ₁ and X ₂ is halide and the other is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (VII);

3) reduction of the enone (VII) to form a cyclic ketone (Villa);

4) formation of the oxime derivative (IXa) of the cyclic ketone (Villa); and

5) reductive acylation and deprotection to form the enamide (III).

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5):

1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is selected from (l-6C)alkyl, -SiL ₃ (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO ₂ (I -6C)alkyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein either a) R ₁ is an imine; X ₁ is halide; X ₂ is halide; R ₂ is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) R ₁ is an acetal; one OfX ₁ and X ₂ is halide and the other is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (FV) to form an enone (VII);

3) reduction of the enone (VII) to form a cyclic ketone (Villa);

4) formation of the oxime derivative (IXa) of the cyclic ketone (Villa); and 5) reductive acylation and deprotection to form the enamide (III).

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5):

1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is selected from (l-6C)alkyl, -SiL ₃ (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO ₂ (I -6C)alkyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group;

R ₁ is an imine; X ₁ is halide; X ₂ is halide; R ₂ is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (VII);

3) reduction of the enone (VII) to form a cyclic ketone (Villa);

4) formation of the oxime derivative (IXa) of the cyclic ketone (Villa); and

5) reductive acylation and deprotection to form the enamide (III).

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is selected from (l-όC)alkyl, -SiL ₃ (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO ₂ (I -6C)alkyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein Ri is an acetal; one of Xi and X ₂ is halide and the other is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (VII);

3) reduction of the enone (VII) to form a cyclic ketone (Villa);

4) formation of the oxime derivative (IXa) of the cyclic ketone (Villa); and

5) reductive acylation and deprotection to form the enamide (III).

hi a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (FV) wherein each R is (l-6C)alkyl and wherein P is benzyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein either a) R ₁ is an imine; Xi is halide; X ₂ is halide; R ₂ is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) R ₁ is an acetal; one OfX ₁ and X ₂ is halide and the other is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B

atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (Vila); 3) reduction of the enone (Vila) to form a cyclic ketone (Villa);

4) formation of the oxime derivative (IXa) of the cyclic ketone (Villa); and

5) reductive acylation and deprotection to form the enamide (III).

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5):

1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is benzyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein either a) R ₁ is an imine; X ₁ is halide; X ₂ is halide; R ₂ is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) R ₁ is an acetal; one OfX ₁ and X ₂ is halide and the other is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (Vila); 3) reduction and deprotection of the enone (Vila) to form a cyclic ketone (VIII);

4) formation of the oxime derivative (IX) of the cyclic ketone (VIII); and

5) reductive acylation to form the enamide (III).

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is benzyl;

by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an imine; X ₁ is halide; X ₂ is halide; R ₂ is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (Vila);

3) reduction and deprotection of the enone (Vila) to form a cyclic ketone (VIII);

4) formation of the oxime derivative (IX) of the cyclic ketone (VIII); and

5) reductive acylation to form the enamide (III).

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5):

1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is benzyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R ₁ is an acetal; one OfX ₁ and X ₂ is halide and the other is -B(OH) ₂ or B(OR ₃ ) ₂ (wherein each R ₃ is independently (l-4C)alkyl or wherein the two -OR ₃ groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R ₂ is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (Vila);

3) reduction and deprotection of the enone (Vila) to form a cyclic ketone (VIII); 4) formation of the oxime derivative (IX) of the cyclic ketone (VIII); and

5) reductive acylation to form the enamide (III).

In a further embodiment of the invention, is provided a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is benzyl;

by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group;

R ₁ is an imine; X ₁ is bromide; X ₂ is bromide; R ₂ is an acetal or thioacetal; the transition metal is copper;

2) intramolecular cyclisation of the keto-aldehyde compound (IV) to form an enone (Vila);

3) reduction and deprotection of the enone (Vila) to form a cyclic ketone (VIII) using hydrogen with palladium catalysis;

4) formation of the oxime derivative (IX) of the cyclic ketone (VIII); and 5) reductive acylation with iron and acetic acid to form the enamide (III).

There follow particular and suitable values for certain substituents and groups referred to in this specification. These values may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore, or hereinafter. For the avoidance of doubt each stated species represents a particular and independent aspect of this invention.

Suitable values for (l-4C)alkyl include methyl, ethyl, isopropyl, propyl, butyl, isobutyl and tertiarybutyl; suitable values for (l-6C)alkyl include (l-4C)alkyl, pentyl, cyclopentyl, hexyl and cyclohexyl; suitable values for -CO ₂ (I -4C)alkyl include -CO ₂ CH ₃ , -CO ₂ CH ₂ CH ₃ and -CO ₂ tBu; suitable values for -CO ₂ (I -6C)alkyl include -CO ₂ (I -4C)alkyl and -C0 ₂ pentyl, suitable values for -C(O)(I -4C)alkyl include -C(O)CH ₃ , and -C(O)CH ₂ CH ₃ ; suitable values for -C(O)(I -6C)alkyl include -C(0)(l-4C)alkyl and -C0 ₂ pentyl.

The term 'aryl' means an aromatic carbocyclic ring, optionally substituted by 1, 2, or 3 substituents independently selected from (l-4C)alkyl, halo.

When two RO groups together form a (l-4C)alkylenedioxy group, the (1- 4C)alkylenedioxy group is, for example, methylenedioxy -(0CH ₂ O)- or ethylenedioxy - (OCH ₂ CH ₂ O)-. For example, when two adjacent RO groups form an ethylenedioxy group the enamide of formula (III) is of the formula (Ilia) or (IHb):

IHb

When herein it is stated that two -OR ₃ groups together with the B atom to which they are attached form a ring, the ring so formed may be, for example a 5 to 7 membered ring that contains a group of the formula — O-B-O- in the ring and which is linked to the group to which it is attached via the B group, he ring so formed is optionally substituted on carbon by one or more methyl groups. Representative examples of such rings include but are not limited to:

Certain compounds of the formulae (IV), (V), (VI), (VII) ₃ (VIII) and (IX) described hereinbefore are novel and provide further independent aspects of the invention. Particular compounds of these formulae are those wherein (as appropriate) R is (l-6C)alkyl and P is benzyl. Further particular compounds of these formulae are those wherein R is methyl and P is benzyl.

Examples

The invention will now be illustrated in the following non limiting examples, in which standard techniques known to the skilled chemist and techniques analogous to those described in these examples may be used where appropriate, and in which, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and work up procedures were carried out after removal of residual solids such as drying agents by filtration;

(ii) all reactions were carried out under an inert atmosphere at ambient temperature, typically in the range 18-25 ⁰ C, with solvents technical grade under anhydrous conditions, unless otherwise stated; (iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated;

(iv) the term ReI. VoIs (or VoIs) refers to the relative amount of solvent used in millilitres, relative to the amount of the main reaction substrate in grams.

(v) the structure of the end-products of the invention were generally confirmed by NMR and mass spectral techniques; magnetic resonance chemical shift values were measured in

deuterated dimethyl sulphoxide (unless otherwise stated) on the delta scale (ppm downfield from tetramethylsilane); proton data is quoted unless otherwise stated; spectra were recorded at 500 MHz on a on a Bruker DRX500 spectrometer, at 400 MHz on a Bruker DPX400 spectrometer or at 200 MHz; and peak multiplicities are shown as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; tt, triple triplet; q, quartet; tq, triple quartet; m, multiplet; br, broad; LCMS were recored on a Waters ZQ Mass Spec Detector, LC column was a SB C8 150mm x 3.0 mm 3.5um (Agilent Zorbax), detection with a HPl 100 with a Diode Array Detector; unless otherwise stated the mass ion quoted is [M + H] ; fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected.

(vi) each intermediate was purified to the standard required for the subsequent stage and was characterised in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate;

(vii) the following abbreviations may be used hereinbefore or hereinafter:- THF tetrahydrofuran; and butyl acetate BuOAc; and

DMF: dimethylformamide THF is tetrahydrofuran DMSO is dimethylsulfoxide HPLC is high performance liquid chromatography

Step l Compound 1 : l-(4-Benzyloxy-6'-fl,31dioxoIan-2-vI-2',3',4'-trimethoxy-bip henyl-2-yl)- ethanone

Potassium phosphate (1.54 g, 7.25 mmol) was added to a solution of l-[5-benzyloxy-2- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-ethan one (Intermediate 1, 2.55 g, 7.24 mmol) and 2-(2-bromo-3,4,5-trimethoxy-phenyl)-[l,3]dioxolane (Intermediate 2, 1.54 g, 4.83 mmol) in DMF (38 ml, 490.7 mmol). The mixture was purged with argon, tetrakis(triphenylphosphine) palladium(O) (0.28 g, 0.242 mmol) was added and the mixture was heated to 100°C for 18 hours. On completion of the reaction, DMF was removed under vacuum at 45 ⁰ C and ethyl acetate (100 ml) and water (50 ml) were added. The ethyl acetate phase was removed, washed with water (50 ml), dried over magnesium sulfate and concentrated. Purification by column chromatography [ethyl acetate:hexane (15 :85)-»(40:60)] produced the desired product (200 mg) as a film.

¹ H-NMR (200 MHz. CDCl ₂ ) δ: 2.06 (3 H, s), 3.49, 3.79, 3.85 (9 H, 3 x s), 3.65-4.09 (4 H, m), 5.04 (2 H, s), 5.28 (1 H, s) and 6.90-7.42 (9 H, m).

Compound 2: 4'-BenzvIoxy-2'-fl,l-(ethylendioxy)ethyll-4,5,6-trimethoxy- biphenyl-2-carbaldehyde

"Butyllithium (2.39M, 5.17 ml, 0.0123 mol) was added to a stirred solution of 2-(5- benzyloxy-2-bromophenyl)-2-methyl-[l,3]dioxolane (Intermediate 4, 4.12g, 0.0118 mol) in toluene (50 ml) and tetrahydrofuran (5 ml) at -78 ⁰ C under dry nitrogen over 15 min. After 15 min, CuBr.P(OEt) ₃ complex (5.25g, 0.0168 mol) in THF (5 ml) was added over 15 min. After a further 15 min, a solution of (2-bromo-3,4,5-trimethoxy-benzylidene)- cyclohexylamine (Intermediate 3, 4.0g, 0.0112 mol) in THF (15 ml) was added over 15 min. The mixture was then allowed to warm to room temperature over 16 h, then heated to 45 ⁰ C for 48 h. Heating was then discontinued, aqueaous acetic acid (10%, 50 ml) was added, and the mixture was stirred for 1 h. The organic layer was washed with aqueous acetic acid (10%, 50 ml), and brine (2 x 50 ml). The mixture was then filtered through a bed of celite and the resultant solution was evaporated under reduced pressure. The residue was disolved in warm

ethanol (20 ml) and the resultant solution was covered and left at room temperature overnight. Filtration, followed by drying in a vacuum oven at 4O ⁰ C, gave the title product (4.Og, 77% yield [90% strength by NMR] as a pale yellow crystalline solid.

¹ H-NMR (400 MHz, CDCh) δ- 1.45 (3H, s), 3.48-3.54 (IH, m), 3.68 (3H, s), 3.73-3.80 (2H, m), 3.84-3.92 (IH, m), 3.95 (3H, s), 3.96 (3H, s), 5.13 (IH, s), 6.93 (IH, dd), 7.07 (IH, d), 7.32 (IH, s), 7.34-7.44 (3H ₅ m), 7.37 (IH, d), 7.46-7.51 (2H, m), 9.47 (IH, s).

Compound 3: 4'-Benzyloxy-4.,5,6-trimethoxy-2'-(2-inethyl-fl.,31oxathiola n-2-yl)- biphenvI-2-carbaldehyde

2-(5-Benzyloxy-2-bromo-phenyl)-2-methyl-[l,3]oxathiolane (Intermediate 5, 2.0Og, 5.5mmol) was dissolved in THF (30ml) and cooled to -78 ⁰ C. n-Butyl Lithium (2.41ml, ό.Ommol) was added, followed by CuBr ₁ P(OEt) ₃ (2.93g, 8.2mmol) in THF (2ml), at -78 ⁰ C, and (2-bromo-3,4,5-trimethoxy-benzylidene)-cyclohexylamine (Intermediate 3, 2.15g, 6.0mmol).

The reaction mixture was allowed to warm to ambient temperature, and held for 18 hours. The solvent was removed by vacuum distillation, and the residue partitioned between toluene (50ml) and 20% aq. acetic acid (50ml) for 1 hour. The organic phase was separated and washed with saturated NaHCO ₃ solution (50ml) and then brine (50ml), then dried over MgSO ₄ . The solvent was removed under vacuum distillation and the residue purified by chromotography (petroleum ether/diethyl ether) to yield a yellow oil (2.0Og, 76%), which crystallised on standing.

The product is isolated as a mixture of diastereoisomers, due to atropisomerism (restricted rotation about the biaryl bond). ¹ H-NMR (400 MHz, DMSO): δ 1.63 & 1.77(s, 3H), 2.52-4.15 (m, 4H), 3.57 & 3.59 (s, 3H), 3.86 & 3.87 (s, 3H), 3.89 & 3.91 (s, 3H), 5.16 (s, 2H), 6.97-7.28 (m, 4H) 7.33-7.53 (m, 5H), 9.34 & 9.37 (s, IH).

Compound 4: 4'-Benzyloxy-4,5,6-triinethoxy-2'-[l-inethoxyiinino-ethvI)-b iphenyl-2- carbaldehyde

5 l-(5-Benzyloxy-2-bromophenyl)-ethanone O-methyl-oxime (Intermediate 6, 2.0Og, ό.Ommol) was dissolved in THF (30ml) and cooled to -78 ⁰ C. n-Butyl Lithium (2.63ml, 6.6mmol) was added, followed by CuBr ₁ P(OEt) ₃ (2.79g, 9.0mmol) in THF (2ml), at -78 ⁰ C, and (2-bromo-3,4,5-trimethoxy-benzylidene)-cyclohexylamine (Intermediate 3, 2.35g, 6.6mmol). The reaction mixture was allowed to warm to ambient temperature, and held for

10 18 hours. The solvent was removed by vacuum distillation, and the residue partitioned between toluene (50ml) and 20% aqueous acetic acid (50ml) for 1 hour. The organic phase was washed with saturated NaHCO ₃ (50ml) then brine (50ml), then dried over MgSO ₄ . The solvent was removed under vacuum distillation and the residue purified by chromotography (petroleum ether/diethyl ether) to yield a brown oil. Trituration with petroleum ether/diethyl

15 ether yielded a white solid (1.2g, 44%).

¹ H-NMR (400 MHz, CDCh): δ 1.80 (s, 3H), 3.66 (s, 3H), 3.69 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 5.13 (s, 2H), 7.02 (dd, IH), 7.09 (d, IH), 7.19 (d, IH), 7.31 (s, IH), 7.32-7.49 (5H), 9.56 (s, IH).

20 Step 1 conversions

Compound 5: 2'-Acetyl-4'-benzyloxy-4,5,6-trimethoxy-biphenyl-2-carbaldeh yde

Method a):

4'-Benzyloxy-4,5,6-trimethoxy-2'-(2-methyl-[l,3]oxathiola n-2-yl)- biphenyl-2-carbaldehyde 25 (Compound 3, 20.Og, 41.6mmol) was dissolved in 10% aqueous acetone (400ml). Methyl iodide (104ml, 1.665mol) was added and the reaction mixture heated to reflux for 12hours.

The solvent was removed by vacuum distillation and the residue partitioned between dichloromethane (200ml) and saturated NaHCO ₃ .solution (200ml). The organic phase was washed with brine (200ml), dried over MgSO ₄ and the solvent removed by vacuum distillation to yield the product as a brown oil (16.8g, 96%). ¹ H NMR (400 MHz, CDCh) δ: 2.32 (3H, s), 3.55 (3H, s), 3.95 (3H, s), 3.96 (3H, s), 5.16 (IH, s), 7.13-7.15 (2H, m), 7.34 (IH, s), 7.35-7.50 (6H, m,), 9.63 (IH, s).

Method b)

A stirred mixture of 4'-benzyloxy-2'-[l,l-(ethylendioxy)ethyl]-4,5,6-trimethoxy-b iphenyl-2- carbaldehyde (Compound 2, 1.0 g, 0.002 mol) in ethanol (10 ml) was warmed to 65 ⁰ C and treated with concentrated hydrochloric acid (~10M, 0.1 ml). Water (5 ml) was then added and the clear solution was stirred for 2 h. The mixture was then concentrated under reduced pressure, diluted with toluene (50 ml) and washed with brine (2 x 30 ml). The organic extract was then dried with magnesium sulfate and evaporated under reduced pressure. Purification of the residue by flash chromatagraphy (4:1, cyclohexane/EtOAc) provided the title compound, as an oil, 0.8g, 88% yield.

¹ H NMR (400 MHz, CDCh) δ: 2.32 (3H, s), 3.55 (3H, s), 3.95 (3H, s), 3.96 (3H, s), 5.16 (IH, s), 7.13-7.15 (2H, m), 7.34 (IH, s), 7.35-7.50 (6H, m), 9.63 (IH, s).

Step 2 Compound 6: 3rBenzyloxy-940Jl-trimethoxy-dibenzofa.,clcvcloheptan-5-one

A stirred mixture of 4'-benzyloxy-2'-[l,l-(ethylendioxy)ethyl]-4,5,6-trimethoxy-b iphenyl-2- carbaldehyde (Compound 2, 4.0 g, 0.0078 mol) in ethanol (25 ml) was warmed to 65 ⁰ C and treated with concentrated hydrochloric acid (~10M, 0.39 ml, 0.0039 mol). Water (18 ml) was then added and the clear solution was stirred for 2 h. Potassium carbonate (anhydrous) (1.59 g, 0.0116 mol) was then added and the temperature was raised to 9O ⁰ C. After 5 h the mixture was cooled in an ice bath for 30 min. then filtered under reduced pressure. The enone was collected as a yellow solid and washed with aqueous HCl (IM, 100 ml), then water (100 ml).

It was then dried in a vacuum oven at 42 ⁰ C overnight to give the title compound (3.16g, 91% yield).

¹ H NMR (400 MHz, CDCh) δ: 3.44 (3H, s), 3.95 (3H, s), 4.00 (3H, s), 5.17 (2H, s ), 6.53 (IH, d), 6.78 (IH, s), 7.17 (IH, dd), 7.19 (IH, d), 7.30-7.50 (6H, m), 8.00 (IH, d).

Step 1 and 2

Compound 6: 3-Benzyloxy-94041-trimetIioxy-dibenzora,c|cvcloIiepten-5-one

Method a) l-[5-benzyloxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)-phenyl]-ethanone Potassium phosphate (0.75 g, 3.53 mmol) was added to a solution of 2-bromo-3,4,5- trimethoxybenzaldehyde (Intermediate 7, 0.63 g, 2.29 mmol) and 2-acetyl-4- benzyloxyphenyl boronic acid (Intermediate 8, 0.93 g, 3.44 mmol) in DMF (18 ml, 232.5 mmol). The mixture was purged with argon, tetrakis triphenylphosphine palladium(O) (0.28 g, 0.242 mmol) added and the mixture heated to 100 ⁰ C for 20 hours. On completion of the reaction, DMF was removed under vacuum at 45°C and ethyl acetate (250 ml) and water (250 ml) were added. The ethyl acetate phase was washed with water (250 ml), dried over magnesium sulfate and concentrated under vacuum. Purification by column chromatography [ethyl acetate:hexane (15:85)— »(40:60)] produced the title product (23.6 mg) as a film.

Method b)

"Butyllithium (2.39M, 5.17 ml, 0.0123 mol) was added to a stirred solution of 4-benzyloxy-2- [l,l-(ethylendioxy)ethyl]-bromobenzene (Intermediate 4, 4.12g, 0.0118 mol) in a mixture of toluene (50 ml) and tetrahydrofuran (5 ml) at -78 ⁰ C under dry nitrogen over 15 min. The mixture was stirred for 15 mins before addition of CuBr.P(OEt) ₃ complex (5.25g, 0.0168 mol) in THF (5 ml) over 15 min. After a further 15 min, a solution of (2-bromo-3,4,5-

trimethoxy-benzylidene)-cyclohexylamine (Intermediate 3, 4.Og, 0.0112 mol) in THF (15 ml) was added over 15 min. The mixture was then allowed to warm to room temperature over 16 h, then heated to 45 ⁰ C for 48 h. Heating was then discontinued, IM hydrochloric acid (50 ml) was added, and the mixture was stirred at room temperature for 2 h, followed by heating at reflux for 4 h. The organic layer was washed with hydrochloric acid (10%, 50 ml), and brine (2 x 50 ml), dried (MgSO ₄ ) and evaporated under reduced pressure. The residue was dissolved in ethanol (25 ml) and water (15 ml), then treated with potassium carbonate (anhydrous) (0.76 g, 0.0056 mol). The temperature was then raised to 9O ⁰ C and stirred at this temperature for 5.5 h. The mixture was cooled in an ice bath for 30 min, then filtered under reduced pressure. The product was collected as a dark yellow solid, washed with ethanol (30 ml), then dried in a vacuum oven at 42 ⁰ C overnight to give the title compound (4.16g). ¹ H NMR (400 MHz. CDClO δ: 3.44 (3H, s), 3.95 (3H, s), 4.00 (3H, s), 5.17 (2H, s), 6.53 (IH, d), 6.78 (IH, s), 7.17 (IH, dd), 7.19 (IH, d), 7.30-7.50 (6H, m), 8.00 (IH, d)

Step 3

Compound 7; 3-Hvdroxy-9,10Jl-trimethoxy-dibenzo[a,clcycloheptan-5-one

Method a) 3-Benzyloxy-9, 10, 11 -trimethoxy-dibenzo[a,c]cycloheptan-5-one (Compound 6, 1.O g, 0.0025 mol) and palladium hydroxide on carbon catalyst (0.1 g) were charged to a 200 ml hydrogenation vessel. THF (25 ml) and acetic acid (200 μL) were added and the flask was set-up on the hydrogenator. The vessel was purged with nitrogen (3 times), then with hydrogen (3 times), then left to react at 0.2 bar hydrogen pressure with stirring at lOOOrpm. After 19 h the mixture was filtered through celite and the solids were washed with dichloromethane (100 ml). The solvents were then evaporated from the filtrate and the residue crystallised from methanol (25 ml). The product was collected by filtration under reduced pressure and dried at 42 ⁰ C in a vacuum oven, to provide, 0.62 g. 79% yield,

¹ R NMR (400 MHz. CDClV) δ: 2.50-3.50 (4H, m), 3.50 (3H, s) ₅ 3.89 (3H, s), 3.90 (3H, s), 6.24 (IH, s), 6.60 (IH ₃ s), 7.03 (IH, dd), 7.09 (IH, d), 7.47 (IH, d);

m/z (Εlectrosprav) 315 ([M + H] ⁺ , 100%);

Found [M + H] ⁺ 315.1242 Ci ₈ Hi ₉ O ₅ requires 315.1232.

Method b)

3-Benzyloxy-9,10,ll-trimethoxy-dibenzo[a,c]cycloheptan-5- one (Compound 6, 2.0Og, 4.97mmol) was dissolved in THF (40ml). Pd/C (10%) (0.2Og, 10% charge) was added and the reaction mixture stirred under H ₂ (1 atmosphere pressure, room temperature) for 24 hours. The catalyst was filtered and the solvent was removed by distillation to yield a waxy solid which was triturated with diethyl ether to yield pure product (1.65g, 82%).

Step 4

Compound 8: 3-Hydroxy-9 JOJlMrimethoxy-dibenzofa.cicycIoheptan-S-one oxime

Method a)

A mixture of 3-hydroxy-9,10,ll-trimethoxy-dibenzo[a,c]cycloheptan-5-one_( Compound 7, 21.39g, 0.064 mol), hydroxylamine hydrochloride (7.51g, 0.108 mol) and sodium acetate (15.66g, 0.191 mol) in absolute ethanol (600ml) was heated under reflux for 10 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and then evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate (800ml) and water (300ml) and the separated organic layer was washed with saturated aqueous sodium bicarbonate solution (200ml) and saturated brine (200ml) and then dried (Na ₂ SO ₄ ). The solvents were removed in vacuo to leave a pale brown foam which was dissolved in hot methanol (200ml) and the resulting mixutre was then allowed to cool slowly to room temperature allowing the product to crystallise. The mixture was cooled to 0-5°C for 2 hours,

filtered and the filter cake washed with cold methanol (2 x 20ml). The oxime was obtained as a white solid and as a ~3: 1 mixture of isomers (17.21g, 80%).

¹ H-NMR (400 MHz. dβDMSO): δ 2.41-3.21 (4H, m), 3.47 (3H, s), 3.74 (3H, s), 3.81 (3H, s), 6.65-6.89 (3H, m), 7.24 (IH, d, J 9.0), 9.56 (IH, s), 10.98 (IH, s). Accurate Mass : 330.1351 (C ₁₈ H ₂₀ NO ₅ = 330.1341)

Method b)

Pyridine (6.43 ml, 0.079 mol) was added in one portion to a stirred slurry of 3-hydroxy-

9,10,1 l-trimethoxy-dibenzo[a,c]cycloheptan-5-one (Compound 7, 10.70 g, 0.032 mol) and hydroxylamine hydrochloride (3.56 g, 0.054 mol) in absolute ethanol (100 ml) at room temperature. The resulting mixture was heated under reflux for 3 h. Water (250 ml) was then added at a constant rate over 10 min with continued heating. Heating was continued until the mixture had reached reflux and was then allowed to cool slowly to room temperature overnight. The mixture was cooled to 0-5°C for 2 h and filtered. The filter cake was washed with aqueous ethanol (1:3, EtOH, H ₂ 0, 1 x 20 ml) and then dried in a vacuum oven (40°C) overnight. The product was obtained as an off white solid (major isomer >90%) (10.72 g, 93%).

¹ H-NMR (400 MHz. dgPMSO) (major isomer): δ 2.41-2.73 (3H, m), 3.03 (IH, ddd), 3.45 (3H, s), 3.73 (3H, s), 3.81 (3H, s), 6.75 (IH, s), 6.76 (IH, d), 6.83 (IH, dd), 7.22 (IH, d), 9.54 (IH, s), 10.95 (IH, s).

Step 5

Compound 9 ; N-(3-Hydroxy-9,l 0,11 -trimethoxy-TH-dibenzo f a,c] cyclohepten-5-vD- acetamide

Acetic anhydride (10.74ml, 0.114 mol) was added in one portion to a stirred slurry of 3^ hydroxy-9,10,11-trimethoxy-dibenzo [a,c] cycloheptan-5-one oxime (Compound 8, 15.35g,

0.046 mol) in glacial acetic acid (150ml) at room temperature and the resulting mixture was stirred for 40 minutes. Iron powder (3.09g, 0.054 mol) was then added in one portion and stirring was continued for a further 4 hours. The solvents were removed in vacuo and the brown solid residue was partitioned between ethyl acetate (1000ml) and saturated aqueous sodium bicarbonate solution (300ml) (caution: effervescence!) and the mixture stirred vigorously for 10 min. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution (300ml) and saturated brine (200ml) and dried (Na ₂ SO ₄ ). The organic layer was concentrated by distillation under atmospheric pressure until 800ml of distillate had been collected. The resulting slurry was allowed to cool slowly to room temperature and then cooled to 0-5°C for 3 hours. The product was isolated by filtration and the filter cake washed with cold ethyl acetate (2 x 15ml) and then dried in a vacuum oven (4O ⁰ C). The enamide was obtained as a white solid (11.17g, 64%). ¹ H-NMR f400 MHz. dgPMSO): δ 1.91 (3H, s), 2.45 (IH, dd), 2.99 (IH, dd), 3.41 (3H, s), 3.73 (3H, s), 3.80 (3H, s), 6.37 (IH, dd), 6.72 (IH, s), 6.76 (IH, dd), 6.88 (IH, d), 7.43 (IH, d), 9.25 (IH, s), 9.52 (IH, br. s).

Accurate Mass : 356.1517 (C ₂₀ H ₂₂ NO ₅ = 356.1498)

Intermediate 1 l-f5-BenzyIoxy-2-(4,4,5,5-tetramethyl-[l,3-.21dioxaborolan-2 -yl)-phenyll-ethanone

Pinacol (1.62 g, 13.7 mmol) was added to a solution of 2-acetyl-4-benzyloxyphenyl boronic acid (3.7 g, 13.7 mmol) in toluene (35 ml). The reaction mixture was stirred at ambient temperature for 16 hours then concentrated under vacuum to yield the product as a solid [3.6 g, 75% (by HPLC area %)] .

¹ H-NMRqOO MHz. CDCl ₃ V δ 1.42 (15H, s), 5.12 (2H, s) and 7.09-7.48 (8H, m).

2-Acetyl-4-benzyloxyphenyI boronic acid (Intermediate 8)

5 t-Butyl methyl ether (153 ml, 1283 mmol) and dilute hydrochloric acid [a solution of 37 % hydrochloric acid (15 g, 158.26 mmoles) in water (153 ml, 8501 mmol)] were added to 4- Benzyloxy-2-(2-methyl-[l,3]dioxolan-2-yl)-phenyl boronic acid (9.8 g, 31.14 mmol). The mixture was stirred at ambient temperature for 3 hours. On completion of the reaction, the two phases were separated and the aqueous phase extracted with t-butyl methyl ether (80 ml,

10 672.6 mmol, 6.06 equiv). The combined organic phases were washed with water and the phases separated to yield an organic phase containing the product. The organic phase was dried over magnesium sulfate and the solution was concentrated under vacuum to give the product in 77% strength. The product was further purified by trituration with hexane / toluene. ¹ H-NMR (200 MHz, CDClO: δ 2.62 (3 H, s), 5.15 (2 H, s) and 7.10-7.95 (8 H, m).

15

4-Benzyloxy-2-(2-methyl-fl,31dioxolan-2-yl)-phenyl boronic acid

n-Butyllithium in hexane (28.45 ml, 2.5M, 71 mmol) was added dropwise to a cooled (-70 ⁰ C) 20 solution of 2-(5-benzyloxy-2-bromoplienyl)-2-methyl-[l,3]dioxolane (21.6 g, 62 mmol) in THF (100 ml) over 30 minutes. The reaction mixture was stirred at -70°C for 1 hour before the dropwise addition of trimethylborate (7.95 ml, 71 mmol) over 2 minutes. The mixture was then allowed to warm to ambient temperature and stir for 18 hours. Water and t- butylmethylether were then added to the mixture and the organic layer separated. The aqueous 25 layer was then extracted with t-butylmethylether and the combined organic layers concentrated under vacuum (40°C, ~5mm Hg) to give a white solid. The solid was then washed with hexane to give the product [92% yield, 100% strength (by HPLC area %)].

¹ H-NMR (200 MHz. CDCM: δ 1.52 (3H, s), 3.80-4.14 (4H, m), 5.11 (2H, s) and 6.90-8.00 (8H, m).

2-(5-Benzyloxy-2-bromophenyl)-2-methvHl.,31dioxolane

Ethylene glycol (23.8 g, 379.3 mmol) and para-toluenesulfonic acid monohydrate (2.44 g, 12.6 mmol) were added to a solution of 2-bromo-5-benzyloxy-acetophenone (40.0 g, 126.4 mmol) in toluene (500 ml). The solution was heated under reflux with stirring in a 3 -neck round-bottomed flask fitted with a Dean-Stark receiver for 3 hours. The reaction mixture was then cooled to room temperature. The mixture was transferred to a separating funnel and sodium carbonate solution (IM, 500 ml) was added. The mixture was agitated and two phases formed. The organic layer was separated and washed with water (2 x 500 ml). The organic layer was separated, dried (MgSO ₄ ) and concentrated in a rotavapor to afford a white solid. This was dried in a vacuum oven at 40°C to give the desired product (42.34g). ¹ H-NMR (200 MHz, CDCM: δ 1.80 (3 H, s), 3.65-4.10 (4 H, m), 5.05 (2 H, s) and 6.60-7.5 (8 H, m). [MH+] C ₁₇ H ₁₈ BrO ₃ calcd = 349.0439, found 349.0468

Z-Bromo-S-benzyloxyacetophenone

N-Bromosuccinimide (69.8 g, 0.39 mol) was added to a solution of 3-benzyloxyacetophenone (80 g, 0.35 mol) in acetonitrile (300 ml) under nitrogen. The initial slurry was warmed to 6O ⁰ C with stirring, slowly becoming a homogeneous black solution. After 4 hours the acetonitrile was distilled off, the residue diluted with toluene (50 ml) and the solvent again distilled off. The mixture was then diluted with toluene (200 ml) and washed with IM sodium thiosulfate (2 x 300 ml). The organic layer was then separated, dried (MgSO ₄ ) and

concentrated under vacuum (4O ⁰ C, ~5mm Hg). The residue was then dissolved in toluene (100 ml) and washed with IM potassium carbonate (2 x 100ml). The organic layer was then separated, dried (MgSO ₄ ) and concentrated. This produced the crude product (112.6g, 76% strength by HPLC area %) from which 20 g was purified by flash column chromatography 5 (hexane:ethyl acetate 95:5) and 20 g was recrystallised from heptane. This gave the pure product [(16.6 g, 80% yield, 92 % strength; by column chromatography) or (13.8g, 70% yield, 97% strength; by crystallisation)] as white crystals.

¹ H-NMR (200 MHz, CDClQ δ: 2.62 (3 H, s, CH ₃ ), 5.06 (2 H, s, PhCH ₂ ) and 6.86-7.52 (8 H, m, 5 x PhC-H & 3 x ArC-H). 10

3-Benzyloxyacetophenone

Potassium carbonate (151.2 g, 1094 mmol) was added to a solution of 3- hydroxyacetophenone (99.8g, 729.3 mmol) in DMF (400 ml). The solution was heated to

15 90°C with stirring. Benzyl chloride (96.9 g, 765.8 mmol) was then added from a syringe pump over 5 hours. After 6 hours, the reaction mixture was cooled to ambient temperature. The mixture was transferred to a round-bottomed flask and ~300 ml of DMF removed by evaporation under reduced pressure. Ethyl acetate (450 ml) was then added followed by water (600 ml). The organic layer was separated and washed with water (5 xlOOml). The organic

20 layer was separated, dried (MgSO ₄ ) and was concentrated to give the desired product (148.9

S)-

¹ H-NMR (200 MHz. CDClQ δ: 2.59 (3 H, s), 5.11 (2 H, s) and 7.13-7.52 (9 H, m). [MH+] C ₁₅ H ₁₅ O ₂ calcd = 227.1072, found 227.1087

Intermediate 2 2-(2-Bromo-3,4,5-trimethoxyphenvl)- Fl ,31 dioxolane

p-Toluenesulfonic acid (3.5 g, 0.018 mol) was added to a solution of 2-bromo-3,4,5- trimethoxybenzaldehyde (Intermediate 7, 50 g, 0.18 mol) and ethylene glycol (40 ml, 0.73 mol) in toluene (500 ml). The reaction mixture was heated to reflux for 6 hours then cooled and left at ambient temperature for 16 hours. The reaction was again heated to reflux for 5 hours, then potassium carbonate (5 g, 0.036 mol) followed by water (50 ml) were added. The mixture was separated and the organic layer washed with water (7 x 100 ml). The organic layer was t dried (MgSO ₄ ) and concentrated under vacuum to give the product [98% yield, 96% strength (by HPLC area %)] as a tan coloured oil.

¹ H-NMR (200 MHz, CDCl ₃ ): δ 3.87 (6H, s), 3.88 (3H, s), 4.05-4.19 (4H, m), 6.04 (IH, s) and 6.99 (IH ₅ s).

Intermediate s (2-Bromo-3,4,5-trimethoxybenzylidene)-cγclohexylamine

A stirred solution of 2-bromo-3,4,5-trimethoxy benzaldehyde (Intermediate 7, 35 g, 0.127 mol) and cyclohexylamine, in toluene (175 ml) was heated at reflux under a Dean-Stark trap for 2 h. The solution was concentrated under vacuum and the residue was dissolved in isopropanol (70 ml) and cooled in an ice bath to induce crystallisation. Filtration, followed by drying in a vacuum oven at 4O ⁰ C, gave the product (39.7 g, 88% yield) as a white crystalline solid.

¹ H NMR (400 MHz. CDCh) δ : 1.19-1.45 (3H, m), 1.51-1.63 (2H, m), 1.64-1.79 (3H, m), 1.79- 1.88 (2H, m), 3.23-3.33 (IH, m), 3.89 (3H, s), 3.91 (3H, s) ₅ 3.92 (3H, s), 7.41 (IH, s), 8.63 (IH, s).

Intermediate 5 2-(5-Benzyloxy-2-bromophenvD-2-methyl-ri31oxathiolane

2-Bromo-5-benzyloxyacetophenone (75.Og, 0.246mol) was dissolved in toluene (750ml). Mercaptoethanol (68.91ml, 0.983mol) and para-toluene sulfonic acid (4.67g, 24.6mmol) were added and the reaction mixture heated to 65 ⁰ C for 24hrs under vacuum Dean/Stark conditions. The reaction mixture was cooled, washed with saturated NaHCO ₃ (500ml), then saturated brine (2 x 500ml). The solvent was removed by vacuum distillation and the product wa purified by chromotography (petroleum ether/diethyl ether, then toluene/iso-hexane) to yield pure product (27.Og, 30%).

¹ H-NMR (DMSOV δ 1.92 (s, 3H), 2.94 (m, IH), 3.05 (m, IH), 3.81 (m, IH), 4.35 (m, IH), 5.12 (s, 2H), 6.86 (dd, IH), 7.17 (d, IH), 7.30-7.46 (m, 5H), 7.51 (d, IH).

Intermediate 6 l-(5-Benzyloxy-2-bromophenyl)-ethanone O-methyl-oxime

2-Bromo-5-benzyloxyacetophenone (6.0Og, 19.7mmol) was dissolved in methanol (60ml). Pyridine (3.5ml, 43.3mmol) was added, followed by methoxylamine hydrochloride (2.6g, 31.5mmol). The reaction mixture was stirred for 2 hours at ambient temperature. The solvent was removed by vacuum distillation, and the residue partitioned between toluene (60ml) and saturated brine solution (60ml). The two phases were seperated and the organic phase dried over MgSO ₄ . The solvent was removed under vacuum distillation and the residue purified by chromotography (toluene/iso-hexane) to yield a white solid (4.5g, 68.5%).

¹ H-NMR (CDCM: δ 2.20 (s, 3H), 3.98 (s, 3H), 5.04 (s, 2H), 6.82 (dd, IH), 6.93 (d, IH), 7.30-7.45 (6H).

Intermediate 7: 2-Bromo-3,4,5-trimethoxybenzaldehvde

N-Bromosuccinimide (143 g, 0.80mol) was added to a solution of 3,4,5- trimethoxybenzaldehyde (150 g, 0.76 mol), in acetonitrile (750 ml). The reaction mixture was heated to 5O ⁰ C for 1 hour cooled and left at ambient temperature for 54 hours. On completion, sodium thiosulfate solution [24 g, 0.152 mol; in water (115 ml)] was added. The reaction mixture was then concentrated, diluted with dichloromethane (400 ml) and washed with water (2x 200 ml). The organic layer was then separated, dried (MgSO ₄ ), concentrated and recrystallised from iso-propanol (50 ml). The title compound was produced as white crystals [96% yield, 100% strength (by HPLC area %)]. δ _H (200 MHz, CDCl ₃ ) 3.89 (6 H, s), 4.96 (3 H, s), 7.27 (1 H, s) and 10.30 (1 H, s).

Copper (I) bromide - triethyl phosphite complex CuBr + P(OEt) ₃ > CuBr.P(OEt) ₃

Triethyl phosphite (183g, 1.1 mol) was added to a suspension of copper(I) bromide (164.5 g, 1.15 mol) in toluene (500 ml). The mixture was heated at 80°C for 3 h with stirring, then left to cool and settle. The clear solution was decanted from the solid residue and the solvent evaporated on a rotary evaporator at 60°C, to provide copper(I) bromide triethyl phosphite complex as a clear colourless oil, 336g (94% crude yield).