GB2125030A

GB2125030A - Naphthacenequinone synthesis

Info

Publication number: GB2125030A
Application number: GB08312928A
Authority: GB
Inventors: Nero Stefano Del; Paolo Lombardi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1982-08-13
Filing date: 1983-05-11
Publication date: 1984-02-29
Also published as: GB2125030B; GB8312928D0

Abstract

Anthracyclinones of formula <IMAGE> (a> R1 = H, R2 = H, CH3 or alkoxy (b> R1 = OCH3 or alkoxy, R2 = R3 = H (c> R1 = R3 = H, R2 = OH or alkoxy are prepared by condensation of a quinizarin-quinone of formula <IMAGE> R1, R2, R3 as above with 2-( alpha -hydroxyethyl)-1,3-butadiene under Diels-Alder conditions followed by manipulation of the side chains. The anthracyclinones are useful starting materials for the preparation of anti-tumour anthracycline glycosides.

Description

SPECIFICATION Naphthacenequinone synthesis The invention relates to a process for the preparation of daunomycinone and certain analogues thereof.

The compounds which may be prepared according to the process provided have the general formula I

wherein (a) R, represents a hydrogen atom and R2 and R3 are the same and represent hydrogen atoms, methyl groups or alkoxy groups, (b) R2 and R3 both represent hydrogen atoms and R represents a methyl or alkoxy group or (c) R, and R3 both represent hydrogen atoms and R2 represents an alkoxy or hydroxy group. Any alkoxy groups are preferably methoxy groups.

Daunomycinone itself has the formula I in which R, = R3 = H and R2 = OCH3. These compounds are useful in the preparation of certain antibiotic compounds for therapeutical use in the treatment of neoplastic ailments.

The antibiotic compounds have a glycoside moiety at C-7 in place of the hydroxy group and may have a hydroxy-acetyl group at C-9 in place of the acetyl group.

There should particularly be mentioned doxorubicin and 4-demethoxydaunorubicin. The former has the formula I with R, = R3 = H, R2 = OCH3, the C-7 hydroxy group replaced with a daunosaminyloxy group and the C-9 acetyl group replaced with a hydroxyacetyl group. The latter has the formula I with R, = R2 = R3 = H and the C-7 hydroxy group replaced with a daunosaminyloxy group. Both can be prepared from compounds of the formula I, the former as described in United States Patent Specification No. 38031 24 and the latter as described in United States Patent Specification No. 4046878.

The synthesis of the compounds of the formula I must include a step forming the tetracyclic skeleton. One such step involves condensing 1 ,4-dimethoxynaphthalene with a monoalkyl 4acetyl-perhydrophthalate followed by hydrogenation of the ester group and acid catalysed ring closure. Another involves a Diels-Alder reaction between a quinizarin-quinone derivative and a 1,3-butadiene derivative. The process of the invention incorporates a tetracyclic skeletal formation of the latter type.

United States Patent Specifications Nos 4021457 and 4070382 describe the Diels-Alder addition of esters of 2-hydrnxy-1 3-butadiene to a quinizarin-quinone derivative. The esters of 2 hydroxy-1 ,3-butadiene are, however, difficult and expensive to prepare. United States Patent Specifixation No. 4164503 therefore proposes to use 2-halo-1 ,3-butadienes in place of 2 hydroxy-1 ,3-butadienes. In the process of all three United States Patent Specifications the keto group at C-9 of a derivative of 7,10-dihydro-6,1 1-dihydroxy-5,9,12 (8H)-naphthacenetrione must be converted to an acetyl or hydroxyacetyl. This transformation may be effected by reacting the keto group with a metal acetylide followed by hydration of the resulting yne.

The invention provides a process for the preparation of daunomycinone or an analogue thereof having the general formula I as above defined. This process is illustrated by the following reaction scheme.

The first step of the process comprises reacting a quinizarin-quinone having the general formula II wherein R1, R2 and R3 are as above defined with 2-(a-hydroxy-ethyl)-1,3-butadiene.

The quinizarin-quinone II may be prepared as described in United States Patent Specifications Nos 4021457 and 4070382. 2-(a-Hydroxy-ethyl)-1,3-butadiene is inexpensive and readily available, being obtained from 2-chloro,1-3-butadiene (J. Org. Chem., 44, 4788, 1979). This first step is a Diels-Alder reaction, forming the compound Ill wherein R1, R2 and R3 are as above defined which has not only the desired tetracyclic skeleton but also, advantageously a C2 side chain (1-hydroxyethyl) at C-9 for ready manipulation to the acetyl group desired at C-9. If in the quinizarin-quinone Ill R2 = R3 then the Diels-Alder cycloaddition is regiospecific, the diene adding on to the 2,3-double bond rather than the internal 4a,9a double bond.As dienes have been reported to add preferentially to the internal double bond of quinizarinquinones, this is surprisingly advantageous, avoiding the need to block the internal double bond, for example by epoxide formation, see J. Org. Chem., 41, 2296, (1976); J.C.S. Chem. Comm., 1981, 478 and references quoted therein. If the aromatic ring of the quinizarinquinone II is asymmetrically substituted, i.e. if R2 and R3 represent different substituents, the cycloaddition produces a regioisomeric mixture, with the product of addition on to the 2,3-double bond (III) predominating. The mixture of the compound Ill and its regioisomer need not be resolved, at this stage, but may be allowed to continue through the remainder of the process before resolution of the ultimate product into the respective regioisomers in a manner known to those skilled in the art.

The reaction conditions for the Diels-Alder reaction may vary in accordance with the substitution pattern in the aromatic ring of the quinizarin-quinone II. The reaction is preferably carried out in an inert organic solvent. Hydrocarbon solvents, particularly aromatic ones such as benzene, toluene or xylene, are preferred. The reaction temperature may be from 20"C to 100"C, and the reaction may take from 1 hour to 3 days. The product Ill may begin to crystallize during the course of the reaction or after cooling the reaction mixture. It is not necessary to purify the product Ill beyond simple collection by suction. It may already contain some enolized product IV, but this does not need to be removed.

The second step of the process of the invention comprises enolizing the compound Ill. This may be achieved by treatment with an acid, such as acetic acid or stannous chloride, or with a proton acceptor, in a polar organic solvent. It has been found that alkali metal carbonates or bicarbonates induce easy enolization of the compound Ill. The preferred method of conducting this step of the process is to stir a solution or a suspension of the compound Ill in a polar organic solvent with sodium or potassium carbonate or bicarbonate at room temperature.

Generally the end IV crystallizes from the reaction mixture and is then separated by filtration, freed from inorganic salts and dried under reduced pressure.

In the third step of the process according to the invention, the enol IV is epoxidised at the 8,9-double bond by reacting it with a peracid. The reaction is preferably carried out in an organic solvent, chloroform, dichloromethane and acetic acid being suitable. The reaction may be carried out at from O'C to 100"C for from 30 minutes to 10 hours. The resulting oxirane V may readily be obtained from the reaction mixture as a pure crystalline material.

The oxirane V is next transformed into the halo-compound VI wherein R1,R2 and R3 are as hereinbefore defined, X represents a halogen atom and R4 represents a hydrogen atom, a lower alkyl group or a tetrahydropyranyl group or the two substituents R4 together are an isopropylidene or cyclohexylidene group. This procedure may be carried by dissolving or suspending the oxirane in a polar solvent, such as acetonitrile, dioxan, dimethoxy-ethane, dimethylformamide or tetrahydrofuran, and treating it with an alkali metal halide in the presence of an acid. The reaction may proceed at from 10 C to 50"C and may take from 30 minues to 5 hours.The alkali metal halide is preferably a bromide or iodide of sodium, potassium or lithium, and the acid is suitably ptoluene-sulphonic acid or an anhydrous hydrogen halide.

The procedure described above leads to a halo-diol VI in which the C-9 substituents are hydroxy and 1-hydroxyethyl, i.e. R4 = H. It is, however, preferred to cleave the oxirane V in the presence of an excess of a lower alkanol, dihydropyrane 2,2-dialkoxy-propane or 1,1 -dialkoxy- cyclohexane in order to yield a protected halo-diol VI R4 # H).

The next step in the process according to the invention is the reductive dehalogenation of the halo-diol VI to give the protected diol Vlla or the free diol Vllb, depending upon whether the halo-diol VI is protected (R4 + H) or not (R4 = H). This may be carried out by catalytic hydrogenation, reduction with a metal hydride such as tributyltin hydride or reduction with an active metal in an acidic medium, for example zinc in acetic acid. If the protected diol Villa is obtained, it may be converted to the free diol Vllb by known methods of hydrolysis such as mild acidic hydrolysis.

Two alternative routes from the diols Vlla and Vllb to the compound I are available in the process according to the invention. In one route, the phenolic hydroxy groups of the free diol Vllb are optionally protected by lower alkyl or lower alkanoyl groups, such as methyl or acetyl, and the 1-hydroxyethyl group is then oxidised to give the hydroxyketone VIII, wherein R1,R2 and R3 are as above defined and R5 represents a hydrogen atom, a lower alkyl or lower alkanoyl group. The hydroxyketone VIII may be transformed into the compound I by known methods such as bromination and solvolysis (Wong et al, Can. Jour. Chem., 51, 466), followed by deprotection, if necessary, of the phenolic hydroxy groups.

In the second of the alternative routes, the bromination and solvolysis are effected before the oxidation, starting with the protected diol Vlla. The bromination is effected under radical conditions, and the solvolysis of the resulting 7-bromo derivative may be a hydrolysis or an alcoholysis. The optional protection of the phenolic hydroxy groups may be effected before bromination or after solvolysis. This leads to the compound IX, wherein R1, R2, R3 are as above defined, R4 has any of the meanings given above except a hydrogen atom, R, is as above defined and R6 represents a hydrogen atom or an alkyl group. The compound IX is selectively oxidised after removal of the protecting groups R4. If present, protecting groups R5 are removed after the oxidation. This leads to the compound I.

In each of the alternative routes, the protection of the phenolic hydroxy groups may be effected by reaction with a lower alkanoyl chloride in the presence of a base such as pyridine or with a dialkyl sulphate in the presence of an alkali metal carbonate. The preferred protecting group R5 is a methyl group. The removal of the protecting group may be carried out using aluminium chloride (for R5 = alkyl) or sodium methylate (for R5 = alkanoyl). The oxidation is preferably carried out with silver carbonate in an inert solvent such as benzene or with bis(tributyltin) oxide or dibutyltin oxide in a solvent such as dichloromethane.

The process according to the invention is efficient and amenable to large scale production.

The diene is inexpensive and readily available, and its reaction with the quinizarin-quinone II produces the tetracyclic skeleton with a 2 carbon atoms side chain at C-9 for easy manipulation to the desired group. The cyclo-addition favours the 2,3-double bond predominantly in the case of asymmetric R1,R2 and R3 substitution and selectively when the substitution is symmetric.

The compounds lil, IV, V, VI and Vlla as above defined are included within the scoDe of the invention.

The following Examples illustrate the invention.

EXAMPLE 1 9-(1 '-hydroxyethyi)-6a, 7, 10, 1 Oa-tetrahydro-5, 6, 11, 1 2-naphthacenetetrone (III, Rt = R2 = R3 = H) A mixture of 3.9 g of quinizarin-quinone (II, R' = R2 = R3 = H) and 1.87 g of 2-(ahydroxyethyl)-1 ,3-butadiene in 100 ml of dry benzene was refluxed for 2 hours. After cooling, the resulting red precipitate was collected by suction, washed with benzene and dried. There were obtained 3 g (66% yield) of the title product.

m.p.: 166-170"C l.R. (KBr, cm-'): 1710 U.V. (EtOH, nm, D1%m): 415(27.42)318(114.78) 308 (115.26) 249 (608.6) 233 (623.76) N.M.R. (CDCl3, S) : 1.26 (3H, d, J = 7Hz) 1.57 (1H s) 2.38 (4H, m) 3.50 (2H, m) 4.23 (1 H, q, J = 7Hz) 5.62 (1H, m) 7.86 (4H, m) EXAMPLE 2 9-(1 '-hydroxyethyl)-7, 1 O-dihydro-6, 1 1-dihydroxy-5, 12-naphthacenedione (IV, R, = R2 = R3 = H) A solution of 1 g of 9-( 1 '-hydroxyethyl)-6a, 7,1 0-1 Oa-tetrahydro-5, 6,11,1 2-naphthacenetet- rone, prepared as described in Example 1, in 60 ml of dry acetone was stirred with 0.1 9 of anhydrous potassium carbonate for 24 hours.The resulting red precipitate was filtered off, generously washed with distilled water and dried under vacuum at 40"C. There were obtained 930 mg of the title compound (93% yield).

m.p.: 188-190"C l.R. (KBr, cm-l): 3400, 1620, 1585 U.V. (EtOH, nm, E1%m): 259 (1112) 488 (305.5) 521(205) N.M.R. (wet dioxan, S) : 1.29 (3H, d, J = 7Hz) 3.35 (4H, m) 4.20 (1 H, q, J = 7Hz) 5.82 (1H, br s) 7.79 (2H, m) 7.85 (2H, m) 13.05 (2H s) EXAMPLE 3 9-( 1 'hydroxyethyl)-9, 8(8H)-epoxy- 7, 1 O-dihydro-6, 1 1-dihydroxy-5, 12-naphthacenedione (V, R, =R2=R3=H) A suspension of 4,36 g of 9-(1 '-hydroxyethyl)-6, ll-dihydroxy-5, 1 2-naphthacenedione, prepared as described in Example 2, in 250 ml of chloroform was stirred with 4.90 g of m chloroperbenzoic acid at room temperature overnight.The precipitate was filtered off, washed with chloroform and dried, giving 3.1 9 of the title compound. The filtrate and combined washings were washed in turn with a 5% aqueous solution of sodium bisulphite, a saturated aqueous solution of sodium bicarbonate and water. They were then dried over an hydros sodium sulphate, filtered and evaporated under vacuum to yield a further 1.1 g of the title compound (total yield 4.2 g, 92%).

U.V. (EtOH, nm, Er1C9óm) : 257 (1130) 292 (254.5) 487 (282.5) 521(182) M.S. (M/e) : 352, 305, 291 N.M.R. (DMSO, S): 1.22 3H, d, J = 7Hz 3.00 (1 H, m) 3.30 (4H, m) 3.42 (1 H, q, J = 7Hz) 5.01 (1H, burs) 7.83 (2H, m) 8.13 (2H, m) 13.02 (2H, s) EXAMPLE 4 8(8H)-bromo-7, 1 O-dihydro-6, 1 1-dihydroxy-5, 1 2-naphthacene-dione-9-spiro-5'-(2', 2', 4 '-mme- thyl-dioxolan)

To a suspension of 1.4 9 of 9-(1 '-hydroxyethyl)-9, 8(8H)-epoxy-7, 1 0-dihydro-6, ll-dihydroxy- 5,1 2-naphthacene-dione prepared as described in Example 3, in 150 ml of dry acetonitrile (150 ml) were added, in the stated order, 1.46 ml of 2,2-dimethoxypropane, 400 mg of sodium bromide and 905 mg of ptoluenesulphonic acid.The reaction mixture was stirred at room temperature for 3 hours and a net change in colour from red to orange was observed. The solvent was evaporated off in vacuo and the resulting solid was taken up with water, filtered, generously washed with distilled water, dried and crystallized from acetone to yield 1.50 9 of the title product (80% yield).

M.S. (m/e) : 472, 457, 414, 393, 335, 317 N.M.R. (CDCl3, 8, 7:3 mixture of C-8 epimers); 1.35 and 1.45 (3H + 3H, s, 70%) 1.91 (6H, s, 30%) 1.58 (3H, d, J = JHz) 3.14 (2H, ABq, J = 18Hz, d = 6Hz, 30%) 3.17 (2H, ABq, J= 19Hz, D= 14Hz, 70%) 3.61 (2H, m) 4.24 (1 H, q, J = 7Hz) 4.40 (1H, m) 7.75 (2H, m) 8.27 (2H, m) 13.40 and 13.46 (1H + 1H, s, 30%) 13.40 and 13.44 (1H + 1 H, s, 70%) EXAMPLE 5 7,8, 1 O-trihydro-6, 11 -dihydroxy-5, 1 2-naphthacenedione-9-spiro-5'-(2', 2', 4'-trimethyl-dioxolan

A mixture of 2.25 9 of 8(8H)-bromo-7,1 0-dihydro-6, 11-dihydroxy-5,1 2-naphthacenedione-9- spiro-5'-(2',2',4'-trimethyl-dioxolan), prepared as described in Example 4, 1 5 ml of tributyltin hydride and 200 mg of azobisisobutyronitrile in dry toluene (100 ml) was refluxed under nitrogen for 24 hours. The cooled red reaction mixture was filtered through a short column of silica gel, eluting with toluene. The fractions containing the product were combined and evaporated in vacuo to give a red solid which was further purified by washing with small quantities of acetone. 1.32 9 of the title product (70% yield) was obtained.

EXAMPLE 6 9-acetyl-9-hydroxy- 7,8-1 O-trihydro-6, 11 -dimethoxy-5, 1 2-naphthacenedione (VIII, R, = R2 = R3 = H, R5 = CH3).

To a suspension of 2.00 9 of the 7,8,1 0-trihydro-6, 11 -dihydroxy-5, 1 2-naphthacenedione-9spiro-5'-(2',2',4'-trimethyl-dioxolan) in 220 ml of dry acetone were added 2.70 9 of potassium carbonate and 1.7 ml of dimethyl sulphate. The reaction mixture was stirred under reflux for 1 2 hours, cooled, concentrated under vacuum, taken up with benzene, filtered and chromatographed through a short column of silica gel to give 7,8,lO4rihydro-6,1 1-dimethoxy-5,12naphthacene-dione-9-spiro-5'-(2'-2'-4'-trimethyl dioxolan) as a yellow solid (1.97 g, 92%).

NMR (CDCl35, 1:1 mixture of diastereisomers) 1.24and 1.31 (3H, d, J = 6Hz) 1.41 (3 H, s) t.46 and 1.48 (3H, s) 1.70-2.18 (2H, m) 2.61-3.24 (4 H, m) 3.92 (6H, s) 4.11 (1H,q,J=6Hz) 7.71 (2H, m) 8.18 (2H, m) This compound was dissolved in glacial acetic acid (90 ml) and water (15 ml) and refluxed for 1 hour. The cooled reaction mixture was diluted with a saturated aqueous solution of sodium chloride and thoroughly extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo to yield the crude diol as a yellow solid.

M.S. (m/e): 382, 364, 346, 337, 319.

The crude diol was dissolved in anhydrous tetrahydrofuran (100 ml), treated with bis(tributyltin) oxide (6.80 ml) and, after 30 minutes stirring, with the dropwise addition of a solution of bromine (0.65 ml) in tetrahydrofuran (6 ml). After 2 hours of additional stirring, the reaction mixture was concentrated under vacuum and chromatographed through a column of silica gel to give the title product in 63% yield based on 7,8,1 O-trihydro-6, 11 -dihydroxy-5, 1 2-naphthacene dione-9-spiro-5'-(2',2',4'-trimethyl)-dioxolan).

m.p.: 1 84-6 C I.R. (CHCl3, cm-'): 3500, 1710, 1670 NMR (CDCl3, 5): 1.95 (2H, dd, J = 6.7Hz) 2.38 (3H, s) 3.07 (2H, s) 2.90-3.20 (2H, m) 3.85 (3H, s) 3.91 (3H, s) 7.71 (2H, m) 8.17 (2H, m)

Claims

1. A process for the preparation of an anthracyclinone having the general formula I as herein defined, the process comprising reacting under Diels-Alder reaction condition a quinizarinquinone having the general formula II as herein defined with 2-(a-hydroxyethyl)-1,3-butadiene, enolising the resultant compound having the general formula Ill as herein defined by treatment with an acid, a proton acceptor or an alkali metal carbonate or bicarbonate in a polar organic solvent, epoxidising the 8,9-double bond of the resultant compound having the general formula IV as herein defined by reaction with a peracid, opening the oxirane ring of the resultant compound having the general formula V as herein defined by treatment with an alkali metal halide in the presence of an acid, reductively dehalogenating the resultant halo-diol having the general formula VI wherein R1, R2, R3 and X are as defined herein and R4 represents a hydrogen atom by catalytic hydrogenation, treatment with a metal hydride or treatment with an active metal in an acidic medium, optionally protecting the phenolic hydroxy groups of the resultant compound having the general formula Vllb as herein defined by alkylation or alkanoylation and oxidising the 1 3-hydroxy group, and converting the resultant compound of the general formula VIII as herein defined to the anthracyclinone I by bromination and solvolysis and, if necessary, deprotection of the phenolic hydroxy groups.

2. A process for the preparation of an anthracyclinone having the general formula I as herein defined, the process comprising reacting under Diels-Alder reaction conditions a quinizarinquinone having the general formula II as herein defined with 2-(a-hydroxyethyl)-1,3-butadiene, enolising the resultant compound having the general formula Ill as herein defined by treatment with an acid, a proton acceptor or an alkali metal carbonate or bicarbonate in a polar organic solvent, epoxidising the 8,9-double bond of the resultant compound having the general formula IV, as herein defined by reaction with a peracid, opening the oxirane ring of the resultant compound having the general formula V as herein defined by treatment with an alkali metal halide in the presence of an acid and of an excess of a lower alkanol, dihydropyrane, a 2,2dialkoxy-propane or a 1,1 -dialkoxy-cyclohexane, reductively dehalogenating the resultant protected halo-diol having the general formula VI wherein R1, R2, R3, and X are as defined herein and R4 represents a lower alkyl group or a tetrahydropyranyl group or the two substituents R4 together represent an isopropylidene or cyclohexylidene group by catalytic hydrogenation, treatment with a metal hydride or treatment with an active metal in an acidic medium, converting the resultant compound having the general formula Vlla as herein defined to a compound having the general formula IX as herein defined by bromination and solvolysis and optional protection of the phenolic hydroxy groups by alkylation or alkanoylation, the optional protection if carried out being before the bromination or after the solvolysis, removing the protecting groups R4 from the compound IX by mild acid hydrolysis, selectively oxidising the 13-hydroxy group and, if necessary, deprotecting the phenolic hydroxy groups.

3. A process for the preparation of an anthracyclinone having the general formula I as herein defined, the process comprising preparing a protected diol having the general formula Vlla as herein defined according to claim 2, hydrolysing it to a free diol having the general formula Vllb as herein defined, and converting the free diol Vllb to the anthracyclinone I according to claim 1.

4. A process according to any preceding claim in which the reaction of the quinizarin quinone II with 2-(cu-hydroxyethyl)-I ,3-butadiene is carried out in an inert organic solvent.

5. A process according to claim 4 in which the inert organic solvent is an aromatic hydrocarbon solvent.

6. A process according to claim 5 in which the aromatic hydrocarbon solvent is benzene, toluene or xylene.

7. A process according to any of claims 4 to 6 in which the reaction of the quinizarinquinone II with 2-(oi-hydroxyethyl)-1 3-butadiene is carried out at from 20"C to 100"C for from 1 hour to 3 days.

8. A process according to any preceding claim in which the enolisation of the compound Ill is effected by treatment with sodium or potassium carbonate or bicarbonate.

9. A process according to any preceding claim in which the epoxidation of the compound IV is effected in an organic solvent.

10. A process according to claim 9 in which the organic solvent is chloroform, dichloromethane or acetic acid.

11. A process according to claim 9 or claim 10 in which the exploitation of the compound IV is carried out at from O"C to 100"C for from 30 minutes to 10 hours.

12. A process according to any preceding claim in which the opening of the oxirane ring in the compound V is is effected in a polar solvent.

1 3. A process according to claim 12 in which the polar solvent is acetonitrile, dioxan, dimethoxyethane, dimethylformamide or tetrahydrofuran.

14. A process according to claim 1 2 or claim 1 3 in which the opening of the oxirane ring in the compound V is carried out at from - 10"C to 50"C for from 30 minutes to 5 hours.

1 5. A process according to any of claims 1 2 to 14 in which the alkali metal halide is a bromide or iodide of sodium potassium or lithium.

1 6. A process according to any preceding claim in which the acid is ptoluenesulphonic acid or an anhydrous hydrogen halide.

1 7. A process according to any preceding claim in which the reductive dehalogenation of the compound VI is effected by treatment with tributyltin hydride.

1 8. A process according to any preceding claim in which the reductive dehalogenation of the compound VI is effected by zinc in acetic acid.

1 9. A process according to any preceding claim in which the phenolic hydroxy groups are protected by reaction with a lower alkanoyl chloride in the presence of a base.

20. A process according to claim 1 9 in which the base is pyridine.

21. A process according to claim 19 or claim 20 in which the removal of the protecting groups is effected by treatment with sodium methylate.

22. A process according to any of claims 1 to 18 in which the phenolic hydroxy groups are protected by reaction with a dialkyl sulphate in the presence of an alkali metal carbonate.

23. A process according to claim 22 in which the removal of the protecting groups is effected by treatment with aluminium chloride.

24. A process according to any preceding claim in which the oxidation of the 13-hydroxy group is carried out with silver carbonate in benzene.

25. A process according to any of claims 1 to 24 in which the oxidation of the 13-hydroxy group is carried out with bis(tributyltin) oxide or dibutyltin oxide in dichloromethane.

26. A compound of the general formula I as herein defined.

27. A compound of the general formula Ill as herein defined.

28. A compound of the general formula IV as herein defined.

29. A compound of the general formula V as herein defined.

30. A compound of the general formula VI as herein defined.

31. A compound of the general formula Vlla as herein defined.

32. A compound of the general formula Vllb as herein defined.

33. A compound of the general formula VIII as herein defined.

34. A compound of the general formula IX as herein defined.