GB2029828A

GB2029828A - Vincadifformine derivatives

Info

Publication number: GB2029828A
Application number: GB7929639A
Authority: GB
Original assignee: Omnium Chimique SA
Current assignee: Omnium Chimique SA
Priority date: 1978-08-24
Filing date: 1979-08-24
Publication date: 1980-03-26
Also published as: FR2434166A2; DE2934342A1; GB2029828B; FR2434166B2; FR2445332A2; FR2445332B2; DE2934342C2

Abstract

A process for the preparation of vincadifformine and related derivatives which are useful as starting material for the synthesis of, among other alkaloids, vincamine and other similar compounds possessing interesting psychopharmacologic properties. A tetrahydro- beta -carboline (II) is reacted with benzoyl chloride to provide a 2-benzoyl-1,2,3,4,- tetrahydro-9H-pyrido-(3,4-b)-indole (III). Then compound (III) is reduced to give a 2-benzyl- 1,2,3,4-tetrahydro- 9H-pyrido-(3,4-b)-indole (IV). Thereafter, compound (IV) is chlorinated to a chloroindolenine derivative (V) which is treated with a dialkylmalonate salt such as thallium t-butyl methyl malonate to give a dialkyl 3-benzyl-1,2,3,4,5,6- hexahydroazepino-(4,5-b)-indole-5,5- dicarboxylate (VI) in which R5 is H, which is optionally alkylated. Compound (VI) is then partly decarboxylated into an alkyl 3-benzyl- 1,2,3,4,5,6-hexahydro-(4,5-b)-indole- 5-carboxylate which is hydrogenated to give an alkyl 1,2,3,4,5,6- hexahydroazepino-(4,5-b)-indole-5- carboxylate (VIII). In an alternative embodiment, compound (VI) can be hydrogenated to the corresponding dialkyl 1,2,3,4,5,6-hexahydroazepino- (4,5-b)-indole-5,5-dicarboxylate which is then decarboxylated into compound (VIII). Compound (VIII) is condensed with a functionalised aldehyde, typically an epoxy aldehyde or a haloaldehyde such as 1-bromo-4- formyl-hexane, to give vincadifformine or similar pentacyclic derivatives. Various intermediates and functionalised aldehydes are claimed per se. The individual steps of the process are also claimed.

Description

SPECIFICATION Vincadifformine derivatives The present invention relates to a process for making + vincadifformine and derivatives thereof and to new 1 ,2 ,3,4,5,6-hexahydroazepino[4,5-b] i ndole derivatives useful as intermediates.

The vincadifformine derivatives prepared by the process of the invention are of the general formula I

In the above general formula, R1 and R2 are independently hydrogen, hydroxy, acyloxy, carbamate, halo, lower alkoxy or alkyl radical, R3, R4 and R5 are independently lower alkyl or hydrogen, A represents a C1 to C, saturated or unsaturated alkyl chain and which may be substituted by one or more alkyl chain and which may be substituted by one or more alkyl, hydroxy or hydroxy-alkyl radicals.

The term "lower alkyl" as used herein contemplates saturated hydrocarbon radicals, branched or not, containing from one to seven carbon atoms.

Examples of compounds which are prepared in accordance with the present invention are those of formulae Ibli as defined below: lb R1 = 11-OCH3 R2=H R3=CH2-CH3 R4=CH3 R5=H A=(CH2)3lc R1=R2=R5=H R3=CH2-CH3 R4=CH3 A=-CH2-CH(OH)-CH2 Id R1 = R2 = R5 = H R3 = CH2-CH3 R4 = CH3 N-A- = -NH(CH2OH)-CH2- le R, = R2 = R5 = H R3 = H R4 = CH3 A =-CH2CH(CH2-CH3)-CH- lf R1=R2=R5=H R4=CH3 A=-CH2-COH(CH2-COH(CH2-CH3)-CH2lg R1=10-Cl R2=R5=H R3=CH2-CH3 R4=CH3 A=-(CH2)3lh R1=10-Br R2=R5=H R3=CH2-CH3 R4=CH3 A=-(CH2)3li R1=10-OCH3 R2=R5=H R3=CH2-CH3 R4=CH3 A=-(CH2)3 The invention provides a process forthe preparation of # vincadifformine or a + vincadifformine derivative having the general formula I

wherein each of R, and R2 independently are hydrogen, hydroxy, acyloxy, carbamate, alkoxy, alkyl, or halo, R3, R4 and R5 independently are hydrogen o.r C, to C, alkyl, A represents a saturated or unsaturated carbohydryi chain containing from 1 to 7 carbon atoms which may be substituted by-one or more C, to C7 alkyl, hydroxy or C, to C, hydroxy-alkyl radicals which process comprises a) reacting a tetrahydro-p-carboline of the formula:

with benzoyl chloride to form a compound of the formula:

wherein represents a phenyl radical b) reducing the compound of formula III by means of a reducing agent to form a compound of the formula:

c) chlorinating the compound of formula IV to form a compound of the formula::

d) reacting the compound of formula V with a diakyi malonate salt at reflux to form a compound of the formula VI wherein R5 = H

which may be, if desired, N alkylated to give a compound VI wherein P5 is an alkyl group containing from 1 to 7 carbon atoms e) and f), in either order, partially decarboalkoxylating and hydrogenating the compound of formula VI to form a compound of the formula:

g) reacting the compound of formula VIII with a functionalised aldehyde able to form an enammonium intermediate with secondary amines, typically a halo or epoxyaldehyde, optionally in the presence of an organic base such as triethylamine to yield the desired vincadifformine or derivative of formula I.

The invention includes a process for making useful compounds including one or more of steps (a) to (g) above.

The invention also includes as new intermediate compounds those of the formula:

wherein P1 and R2 are hydrogen, hydroxy, acyloxy, carbamate, alkoxy, alkyl or halo or combination of such substituents; P5 represents hydrogen oran alkyl group having 1 to 7 carbon atoms; R represents hydrogen or benzyl; one of R, and R8 may represent hydrogen or carboalkoxy or both R, and RB may represent carboalkoxy wherein the alkoxy group has 1 to 4 carbon atoms and may be different from one another.

The numbering of vincadifformine and its derivatives is in accordance with Le Men and Taylor, Experientia 1965, 21, 508.

Vincadifformine itself (R1, R2 and P5 = H, R3 = CH2CH3, A = -(CH2)3- P4 = CH3) is an alkaloid which is the raw material for the preparation of the vincamine group alkaloids as described in Belgian Patents Nos 772.005 and 848.475. A method for its preparation including several examples is described in British Patent Specification No 2011899 published on 18th July 1 979. The reader may refer to this specification for further guidance regarding the preparation of intermediates used in the processes of this invention.

Vincamine and some of its derivatives are well-known alkaioids used in human therapeutics as psychotropic drugs of high efficiency and possessing a relatively low order of toxicity.

Furthermore, it has been shown that the rearrangement of vincadifformine leading to vincamine may be applied to a large number of other similar derivatives to provide vincamine related compounds (see French Patent Applications Nos 76 22335, 76 22275, Belgian Patent No 816,692 and U.S. Patent Application S.N. 968,147 filed on December 11th, to,1978 in the name of J. Hannart).

For example, 1 0-bromo vincamine and 1 0-bromo vincamone are compounds superior to vincamine when the test of hypoxic anoxia with mice is applied. These compounds can easily be obtained from the corresponding 1 0-bromo vincadifformine.

Two total synthetic methods for vincadifformine are already described in the literature by J.

Kutney et al, J.Amer.Chem.Soc. 90, 3891, 1968 and J. V. Laronze et al, Tetrahedron Letters 491, 1974.

1 1-methoxyvincadifformine (ervinceine) of the formula Ibis an alkaloid occurring in Vinca Erecta and described by D. A. Rakhimov, V. M. Malikov, M. R. Yagudaev and S. N. Yunusov (Khim, prir, Soedin.

226,1970).

Alkylation of ervinceine yields the corresponding N(a) methyl derivative. One enantiomer of this compound, obtained by degradation of vindoline, has recently been converted back to vindoline, the indoline moiety of the "dimeric" oncolytic alkaloid vincaleukoblastine (J. P. Kutney et al. J. Amer. Chem.

Soc. 100, 4220 (1978)).

Pseudo-vincadifformine of formula le is an alkaloid occurring in different Apocynacea and which has been obtained by hemisynthesis (J. P. Kutney, E. Piers and R. T. Brown, J. Amer. Chem. Soc. 92, 1700, 1 970)).

Pandoline of formula If can be obtained from certain plants of the genus Pandaca (M. Zeches, M.

M.Debray, G. Ledouble, L. Lemen-Olivier and J. Le Men Phytochemistry 14 1122, 1975). No total synthesis of this rare alkaloid has been reported.

Severai 1 ,2,3,4,5,6-hexahydroazepino/4,5-b/indoles have been reported in the literature (Dutch Patent Application 65 15701, French Patent 1.524.830--5. B. Hesteretal (J. Med. Chem. 11, 101, 1968)).

Some of these derivatives have interesting pharmacological properties more particularly on the central nervous system.

The present invention aims to obtain vincamine and related polycyclic compounds with high yields, reducing the number of intermediate steps and using cheap reagents.

According to the method of the present invention in a first step a tetrahydro-ss-carboline (Il) when treated with benzoyl chloride yields a 2-benzoyl-l ,2,3 A-tetra hyd ro-9 H-pyrido-[3,4b]-indole (Ill).

wherein Rq and R2 have the same meaning as described above and cP represents a phenyl radical.

In a second step, the reduction of III by a reducing agent such as lithium aluminium hydride (LAH) in tetrahyd rofuran (THF), yields the corresponding 2-benzyl- 1 ,2,3,4-tetra hyd ro-9 H-pyrido(3,4-b)indole IV.

Other protecting groups such as a p-halo-benzyl or benzhydryl group may be used to protect the N/3 of the p carboline II.

In a third step, derivative IV is transformed by the action of tert-butyl hypochlorite or a similar chlorinating agent into a chloroindolenine (V) which is, preferably immediately, treated with a dialkyl malonate salt, e.g. the thallium or sodium salt or an analogous compound, preferably t-butyl methyl thallium malonate

to yield a 3-benzyl-1,2,3,4,5,6-hexahydroazepion (4,5-b) indole-5,5-di(alkyl carboxylate) derivative of the formula VI

wherein R5= H, R1, R2and R4 are as defined above. R4, is a lower alkyl group, typically a methyl, ethyl or t-b-ltyl radicaí.

For this condensation, any solvent inert to the reaction conditions may be used. Benzene and toluene are especially convenient and practical for this use. Compound VI may also be obtained starting from the corresponding y-carboline V' as described in U.S. Patent Application S.N. 936.454 filed on August 24, 1 978.

Compound V' is chlorinated and condensed with the dialkyl sodium, thallium or analogous malonate using the same procedure as starting from V.

The starting raw material V may be for example advantageously prepared from Nbenzylpiperidone, a cheap compound of the formula:

by passing through a N-benzyl piperidone phenyl-hydrazone of the general formula

If desired, compound VI (R5 = H) may be Na alkylated using known procedures for alkylation of indole derivatives (J. Med. Chemistry 11, 101, 1968) to give VI wherein R5 is lower alkyl.

In a fourth step, derivative VI is partly decarboxylated into an alkyl 3-benzyl-1,2,3,4,5,6- hexahydroazepino-(4,5-b)-indole-5-carboxylate (Vlt).

For example, in the case of a t-butyl methyl dicarboxylate this transformation is best achieved by means of trifluoroacetic anhydride ortrifluoroacetic acid. In the case of the corresponding dimethyl derivative, monodecarbomethoxylation is achieved by lithium chloride in dimethylformamide.

In a fifth step, derivative VII is hydrogenated in the presence of a catalyst, typically 5% Pd on charcoal, to remove the protecting benzyl group, yielding an alkyl 1 ,2,3,4,5,6-hexahydroazepino(4,5- b)indole-5-carboxylate derivative of the general formula VIII wherein R5 is hydrogen.

Specific examples of compounds of formulae II to VIII are those having substituents listed below Ia R1 =R2=R=H llb R, = 1-OCH3; R2=R=H llla R1=R2=R=H; lllb R1=11=-OCH3; R3=H; R=CO# lVa R1=R2=R=H; R=CH2# lVb R=11-OCH3; R2=H; R=CH2# Vla-Vlf R3=H Vla R1=R2=H; R4=CH3; R4=t-butyl Vlb R1=8-OCH3; R2=H; R4=R4=CH3 Vlc R1=R2=H; R4=R4=CH3 Vld R1 =H; R2=9-OCH3; R4 = R4, = CH3 Vle R1=H; R2=9-Cl; R4=R4=CH3 Vlf R1=H; R2=9-Br; R4=R4=CH3 Vll R=CH2O; R6=H Vlla R1=R2=H; R4=CH3 Vllb R1=8-OCH3; R2=H; R4=CH2 Vllc R1=H; R2=9-OCH3; R4=CH3 Vlld R1=H; R2=9-Cl; R4=CH3 Vllf R1=H; R2=9-Br; R4=CH3 Vlll R1=H; R6=H Vllla R1=R2=H; R4=CH3 Vlllb R1=8-OCH3; R2=H; R4=CH3 Vlllc R1=H; R2=9-OCH3; R4=CH3 Vllld R1=H; R2=9-Cl; R4=CH3 Vlllf R1=H; R2=9-Br;R4=CH3 In an alternative procedure of the invention, product VI can be hydrogenated in present of P d/c at 5% to yield a dia lkyl-1 ,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5,5-dicarboxylate (VI').

- R2 - R2 - R3 - M R4 - R4' - CH3 which is then partly decarboalkoxylated into VIII and treated as described hereafter or which may be converted to the vincadifformine derivatives I using the procedure described in the hereabove mentioned U. S. Patent Application S.N. 936,454.

The intermediate compounds VI, VI', VII, and VIII constitute a new class of azepino indoles. The azepino-indoles substituted by one or two carboalkoxy groups in position -5 are in fact new intermediates very useful for the synthesis of new indolic alkaloids.

In a sixth step, derivative VIII is condensed with a functionalised aldehyde IX yielding vincadifformine derivatives of formula (I).

By functionalised aldehyde, is meant an aldehyde for which a corresponding tertiary enamine derivative may be N-alkylated intra-molecularly, to form an enammonium salt.

Typically such compounds are halo, aryl or alkylsulfoxy, or epoxy aldehydes having three to fourteen carbon atoms.

Examples of such aldehydes are IXa, IXb, IXc, IXd and IXe which fall within the invention.

Aldehydes further substituted by a hydroxyl group may be used in the equivalent hemi-acetalised form as for IXf.

MesO ^ molyloxy In the case of the reaction of a halo-aldehyde with the azepinoindole VILLI, the intermediate cyclic enammonium of general formula X has been postulated.

In some cases a catalytic amount of an organic base such as triethylamine may be advantageously added to the reaction mixtures.

In effecting the condensation (VIII + aldehyde through X) it has been found preferable to use a solvent such as dry methanol, but other inert solvents to the reaction conditions, for example dry benzene, may be used.

The temperature of the reaction may vary from - 200C to the boiling point of the reaction medium. Preferred temperature ranges include 20O to OOC.

5-bromo-2-ethylpentanal (IXa) which can be used in the last step of the vincadifformine synthesis may be prepared following a new process, hereunder described, which is both practical and convenient.

One acetalises methyl or ethyl 4-formylhexanoate to yield respectively methyl 4dimethoxymethylhexanoate or ethyl 4-diethoxymethylhexanoate which is reduced by means of lithium aluminium hydride into respectively 4-di methoxymethyl- 1 -hexanol or 4-diethoxy-methyi-1 -hexanol.

The alcohol obtained in this way is dehydroxybrominated yielding respectively 1 -bromo-4dimethoxymethyl-hexane and 1 -bromo-4-diethoxymethyl-hexane, which is hydrolysed to yield the required 1 -bromo-4-formyl-hexane or 5-bromo-2-ethylpentanal.

Another preparation of 5-bromo-2-ethylpentanal is also disclosed in W. Oppolzer, H. Hauth, P.

Pfaffli, R. Wenger, Helv. 60,1861(1977).

In the case of the pandoline and epipandoline synthesis, the adequate functionalised aldehyde IXd is obtained following the reactional sequence of scheme I, which is described in details in the examples.

Scheme I

These novel; methods are within the scope of the invention.

Procedures for the preparation of other useful functionalised aldehydes are given in the examples.

The following examples illustrate the invention in a non-limitative way.

EXAMPLE 1 methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino-|4,5b|-indole-5-carboxylate (Vlla) From the dimethyl diester (Vlc) Diester Vlc (9.3 g,24 mmol), lithium chloride (1.3 g, 30 mmol) and water (620 mg, 34 mmol) were dissolved in anhydrous dimethylformamide (20 ml) under nitrogen and the stirred solution was placed in a preheated (1 60-1 650C) oil bath for 1 h. The solution immediately became cloudy and began evolving CO2. After cooling the reaction was poured into water (400 ml) with vigorous stirring.

The gummy solid which formed was collected by filtration through glass wool, dissolved in methylene chloride and dried (MgSO4). After concentrating the solution, the product was purified by column chromatography on silica gel, eluting with methylene chloride. This yielded a solid which was recrystallized from hexane to provide Vlla (6.6 g, 83%) mp: 135-135.5 C.

IR (CHCI): 3480,3075,3045,2940,2840,1740,1600,1500,1460,1435,1350,1275,1230,1220 1200,1163,1026 cm- NMR (CDCI3)a: 2.94 (bs,4 H), 3.24 (m, 2H), 3.67 (s, 3H), 3.88 (s, 2H), 4.16 (m, 1H), 6.97-7.7 (m, 9H). 8.68 (bs, 1 H) Mass spectrum: (80 cV) m/e (relinlensity) 334 (M+. 37), 216 (100), 156 (61),91 (49),42(32) Analysis calculated for C21H22N202 C,75.42;H,6.63;N,8.38 found C,75.63;H,6.90;N,8.41 EXAMPLE 2 Dimethyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5,5-dicarboxylate Vlc To a solution of 0.25 g (0.95 mmol) of N-benzyltetrahydro-ss-carboline (lVa) and 110 l of triethylamine in 7 ml dry benzene, stirring at 5 C under nitrogen, was added dropwise 110 l of tertbutylhypochlorite (0.954 mmol).The mixture was stirred at 5 C for 1 hour 30 minutes, then poured into 3 ml of cold water in a separatory funnel. After gentle shaking the layers were allowed to separate and the H20 layer was discarded. The benzene layer was dried by filtering through a cone of sodium sulfate in phase separation paper. The separatory funnel and filter cone were washed with dry benzene and the benzene filtrate was evaporated under vacuum to 3 ml. Dry benzene was added to a volume of 7 ml.

then 0.335 g (1 mmol) thallium dimethyl malonate was added and the vigorously stirring solution was refluxed under nitrogen for 23 hours. The reaction was then cooled to room temperature and filtered through glass fibre paper and the benzene was evaporated under vacuum. The residue was taken up in dichloromethane and deposited on a column of SiO2 (1.5 cm x 30 cm). Elution with dichloromethane yielded 0.205 g (55%) of a slightly coloured product. Recrystallization from methanol afforded white crystals of product (Vlc), m.p. and mmp 166-168 C.

NMR (CDCl3,8): 2.97 (s, 4H), 3.8 (s, 2H), 3.88 (s, 6H), 3.93 (s, 2H), 7.24-7.8 (m, 9H), 8.64 (bs, 1H).

lR(KBr,vmax): 3510,3010,3000,2950,2940,2920,2880,2825,1750,1705,1490,1450,1440,1435, 1345,1320,1285,1275,1255,1240,1220,(broad,1185,1165,1145,1135,1125,1110, 1090,1075,1055,1035,980,960,935,700,690,670,635 cm-.

IR(CHCl3,vrnax): 3440,3000,1725,1455,1210,(broad) 104,1025,975 cm-.

Mass spectrum (m/e) 392 (M+) EXAMPLE 3 Dimethyl 1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5,5-dicarboxylate (Vl'a) To 1.6 g (4.08 mmol) of the diester benzylamine (Vlc) dissolved in 50 ml of acetic acid was added 0.2 g of 5% palladium on charcoal catalyst. Hydrogenation at atmospheric pressure with vigorous stirring showed termination of hydrogen uptake after 3 hours. The solution was filtered through glass fibre paper and the flask and filter were washed with dichloromethane. The dichloromethane was removed under water aspirator vacuum and the acetic acid was distilled on a vacuum pump with a dry ice/acetone trap. The residue was taken up in dichloromethane, washed with 10% aqueous sodium carbonate dried over potassium carbonate, filtered, and concentrated under vacuum to a white powder of product (Vl'a); 1.231 g (100%).

NMR lCDCl3,#): 2.4 (bs, 1H), 2.9 (t, 2H), 3.1 (t, 2H), 3.66 (2,2H), 3.72 (s, 6H), 6.9-7.5 (m, 4H), 8.66 (bs, 1H) Mass spectrum (m/e) 302 M+.

EXAMPLE 4 Dimethyl-3-benzyl-9-methoxy- 1 ,2,3,4,5,6-hexahydroazepino-(4,5-b)indole-5, 6-dicarhoxylate (Vid) Following the procedure for preparation of the 8-methoxyindoloazepine Vle, the 9-methoxy isomer Vld. mp 128-130 C, was prepared in 65% yield.

NMR (CDCI3): 8.34 (brs, 1H), 7.29 (m, 6H), 6.90 (m, 2H), 3.81 (s, 3H), 3.76 (s, 6H), 3.67 (s, 2H), 2.87 (s, 4H), IR (KBr)Pmax: 3400, 2960, 2840, 1749, 1722, 1480, 1465, 1450, 1430, 1250, 1220, 1140, 1030, 835, 740, 700 cm-'.

Anal. Calcd. for C24H26N205: C, 68.23, H, 6.20, N, 6.63.

Found: C, 68.20, H, 6.24, N, 6.50.

EXAMPLE 5 # 11-methoxyvincadifformine (1b) (Ervinceine) a)Methyl 8-methoxy-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5-carboxylate Vlllb A solution of dimethyl 3-benzyl-8-methoxy-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5,5dicarboxylate Vlb (100 g, 2.37 mmol, obtained from 8-methoxytryptamine by a procedure similar to the one described for Vla), lithium chloride (0.111 9, 2.61 mmol) and 128 yl of water in 10 ml of N,Ndimethylforrmamide was stirred unde nitrogen at 140 C for 2 h. The mixture, which became heterogeneous in this time, was cooled to 20 C, poured into 200 ml of water and extracted with two 75 ml portions of benzene. The benzene solutions were washed with brine, dried over K2CO3, filtered and concentrated under vacuum to 0.747 g (86%) of the monoester Vllb, which has purified by chromatography on silica, eluting with 2.5% methanol in dichloromethane and crystallized from methanol to m- 118-1 190C.

NMR (CDCl3) b: 8.12 (2, 1H), 7.2 (m, 6H), 6.6 (m, 2H), 3.66 (s, 5H), 3.54 (s, 3H), 3.5-3.2 (m, 3H), 3.1-2.6 (m, 4H).

The above N-benzylamino monoester product (0.375 g, 1.03 mmol) and 38 mg of 10% Pd/C catalyst were stirred in acetic acid at 200C under 1 atm. of hydrogen for 1 7 h. After filtration and washing of the catalyst with methanol, the solvents were evaporated under vacuum and the residue dissolved in dichloromethane. Extraction with saturated aq. K2CO3 solution, brine, drying over K2CO3, filtration and concentration gave 0.276 g (97%) of the amino ester Vlllb, which was crystallized from methanol to mp 166-1 670C.

NMR (CDCl3) #; 8.6 (s, 1 H), 7.25 (d, 1 H, J = 8Hz), 6.68 (m, 2H), 3.74 (s, 3H), 3.64 (s, 3H), 3.58-2.70 (m, 7H), 2.30 (brs, 1 H).

Analysis calculated for C1sH18N2o3 C, 65.67; H, 6.61; N, 10.21 found C, 65.45; H, 6.62; N, 10.02 b) 2-ethyl-5-mesyloxypentanallXe To a solution of 2.55 g (0.01 mol) of 4-dimethoxymethyl-1-methanesulfonyloxyhexane in 40 ml of diethylether, 20 ml of 1.2 N HC1 was added and the mixture stirred at reflux for 12 h. Solid potassium carbonate (3 g) was slowly added, the organic layer separated and the aqueous layer extracted with 25 ml of ether.The combined ether solutions were washed with brine, dried over magnesium sulfate filtered and concentrated to 1.66 g of the aldehyde IXe; NMR (CDCI3) ô: 9.57 (d, 1 H), 4.20 (m, 2H), 3.00 (s, 3H), 2.23 (m, 1H), 1.88-1.09 (m, 6H), 0.92 (t, 3H) IR (film)vmax: 2955, 2930, 2870, 2700, 171 5, 1450, 1340, 1 170, 970-910. 820 cm-'.

c) 1 1-methoxyvincadifformine or ervinceine (Ib) A solution of the amino ester Vlllb (100 mg. 0.369 mmol), the mesyloxy aldehyde IXe (0.0835 g, 0.401 mmol) and triethylamine (0.122 g, 1.20 mmol) in 5 ml of anhydrous methanol was stirred at 650C under nitrogen for 17 h. The solvent was evaporated under vacuum and the residual oil chromatographed by PTLC (1.5 mm silica, 3% methanol in dichloromethane). The band of ervinceine was located by spraying the edge of the plate with ceric ammonium sulfate producing a characteristic blue colour. Elution of ervinceine from the separated band with 1:10 methanol in ether and concentration yielded 0.0981 g (73%) of ervinceine Ib. The product crystallized from methanol with melting point 90-920C.

NMR (CDCl3) N: 8.88 (bs, 1 H), 7.04 (d, 1 H), 6.36 (m, 2H), 3.74 (s, 6H), 3.27-0.69 (m, 1 4H), 0.55 (t, 3H).

IR (KBr): 3390,1685,1620,1500,1270 cm- MS (80 eV) m/e: 368 (M+), 124 (base) UV (ethanol)#max (log ) 249 (4.00), 330 (4.12) EXAMPLE 6 + Pandoline et epi-pandoline a) 4-ethyl-5-hydroxypentanoic acid lactone (XII) Aldehyde-esterXI (15.3 g, 97 mmol) was cooled to 0 C in anhydrous methanol (125 ml) and sodium borohydride (1.84 g, 48 mmol) was added at a rate such that the reaction stayed below 200C.

The solution was stirred for 30 min. after the addition was completed and then was poured into water.

The aqueous solution was extracted with ether (3 x 75 ml). The combined extracts were washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The oil was taken up in benzene (200 ml) and p-toluenesulfonic acid (1 g) was added. The solution was refluxed for 15 h. using a Dean-Stark trap filled with anhydrous calcium chloride. After cooling the reaction mixture was washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated. Distillation of the crude material gave lactone XII, bp 70-750C (0.25 mm) (7.2 g, 58%) IR (neat): 2968, 1730, 1180, 1056 cm-' NMR(CDCl3)#: 0.98 (3H, t), 1.2-2.2 (5H, m), 2.58 (2H, m), 4.0 (1 H, d of d), 4.35 (1 H, m).

b) Methyl 4-(phenylselenylmethyl)hexanoate Xlll Diphenyl diselenide (3.65 g, 1 1.7 mmol) was dissolved in freshly distilled dimethylformamide (15 ml) and sodium borohydride (0.89 g, 23 mmol) dissolved in dimethylformamide (10 ml) was carefully added (vigorous evolution of H2) with exclusion of oxygen. The lactone XII (3 g, 23 mmol) was then added and the solution was heated to 1 200C for 8 h. After cooling, the solution was made acidic with 3% HCI and extracted with ether (4 x 50 ml). The ether solution was washed with water, dried (MgSO4) and concentrated. The crude carboxylic acid was esterified by stirring 15 H. at reflux in anhydrous methanol (20 ml) with trim ethyl orthoformate (2.5 g, 23 mmol) and p-toluenesulfonic acid (100 mg).Removal of the methanol in vacuo followed by column chromatography of the residue on silica gel, eluting with hexane until the yellow diselenide band was removed and subsequently with ether gave the pure selenide (3.8 g, 55%). On other runs the yield varied from 25% to 55%. See example 14b' for spectral data.

a') Methyl 4-(methanesulfonyloxymethyl)hexanoate (XII'J Aldehyde Xl (6 g, 38 mmol) was dissolved in methanol (60 ml) and cooled to OOC. Sodium borohydride (0.75 g, 20 mmol) was added slowly keeping the reaction temperature below 10 C. The solution was stirred an additional 15 min. and was then taken up in methylene chloride and washed with water, saturated brine, and dried (MgSO4). Solvent removal in vacuo at 300C gave the crude alcohol derived from the aldehyde XI which was dissolved in methylene chloride (60 ml) with triethylamine (5.2 g, 51 mmol) and cooled to OOC. Methanesulfonyl chloride (5.6 g, 48 mmol) was added dropwise, followed by 30 min. of stirring.An additional 40 ml of methylene chloride was then added and the solution was washed with 3% HCI, saturated aqueous sodium bicarbonate, and dried (MgSO4). solvent removal followed by distillation, bp 145-1 500C (0.3 mm), gave the desired pure mesylate Xll'(7.6 g, 81%), IR (neat): 2965,1734,1350,1175 cm- NMR (CDCl3) d: 1.0 (3H, t), 1.3-1.9 (5H, m), 2.45 (2H, t), 3.1 (3H, s), 3.8 (3H, s), 4.3 (2H, d).

b') Methyl 4-(phenylselenylmethyl/hexanoa te (XIII) Diphenyl diseienide (2.8 g, 8.9 mmol) was dissolved in anhydrous dimethylformamide. Sodium borohydride (690 mg, 18 mmol) was carefully added (vigorous evolution of H2) and the solution changed from orange to nearly colorless as the reduction reached completion. The solution was flushed with nitrogen and the mesylate XII' (2.1 g, 8.5 mmol) was added. The reaction was stirred for 24 h. at room temperature, followed by 3 h. at 450C and then poured into water (1 50 ml). The product was obtained by extracting the aqueous solution with pentane (4 x 75 ml). The pentane extract was washed with water, dried (MgSO4) and concentrated to a yellow oil.Column chromatography on silica gel, eluting with hexane until the yellow diselenide band came off and then eluting with ether, gave the pure selenide XIII (2.2 g, 90%).

IR (neat): 3060,2960,1735,1578 cm- NMR (CDCI3) 8: 0.85 (3H, t), 1.2-1.9 (5H, m), 2.3 (2H, t), 2.9 (2H, d), 3.6 (3H, s), 7.15 (3H, m), 7.44 (2H, m).

c) Methyl 4-ethyl-4-pentenoate (XlV) To a solution of selenide XIII (1.8 g, 6.0 mmol) in methylene chloride (15 ml) at -780C was added m-chloroperbenzoic acid (1.28 g, 85%, 6.3 mmol). The solutiori was allowed to warm to room temperature over 30 min. and was then washed with water, saturated sodium carbonate and dried (MgSO4). The methylene chloride was removed in vacuo and the selenoxide was taken up in carbon tetrachloride (15 ml). Triethylamine (640 mg, 6.3 mmol) was added and the solution was refluxed under nitrogen for 2 h. The reaction was taken up in methylene chloride (25 ml), washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated on a roto-evaporator.The crude olefin XIV was distilled, bp 70-750C (25 mm) to give a colorless oil (630 mg, 74%).

IR (neat): 3070,2960,1740,1160 cm- NMR (CDCI3) 8: 1.0 (3H, t), 2.03 (2H, q), 2.2-2.6 (4H, m), 3.64 (3H, s), 4.7 (2H, d).

d) Methyl 4-ethyl-4-oxyranylpentanoate (XV) At 0 C m-chloro-perbenzoic acid (1.25 g, 85%, 6.1 mmol) was added to a stirred solution of olefin XIV (800 mg, 5.6 mmol) in methylene chloride (8 ml). The solution was allowed to warm to room temperature and stirring was continued for 3 h. The solution was then diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. The crude product was purified by distillation, bp 43 OC (0.3 mm) (730 mg, 82%).

IR (neat): 2965,1735,1165 cm-; NMR (CDCl3) S: 0.95 (3H,t), 1.6 (2H, m), 1.98 (2H, t), 2.4 (2H, t), 2.65 (2H, s), 3.8 (3H, s).

e} 4-ethyl4-oxyranylpentanallXdis obtained from (XV) by a reduction in dichloromethane with a 1 M solution of DIBAL (diisobutylaminealuminium hydride) in hexane at -750C. Procedure is identical with the one described for the synthesis of IXc (Example 1 OB).

f) Pandoline lf and epi-20-pandoline If' Amine Vlla (670 mg, 2.8 mmol) and epoxy-aldehyde IXd (470 mg, 3.7 mmol) were refluxed under nitrogen in methanol (10 ml) for 1.5 h. Thin layer chromatography on silica gel (CH2CI2-MeOH, 99:1) showed two main products (visualized as blue spots by spraying with 10% ceric ammonium sulfate in 85% phosporic acid). The methanol was removed in vacuo and the residue was column chromatographed on silica gel, eluting with methylene chloride-methanol (99:1). The two principal components were obtained.The first, pandoline (If) was recrystallized from acetonitrile (mp 150-151 0C, 290 mg, 30%) and the second, epi-20-pandoline (If') was recrystallized from acetonitrile-water(9:1) (mp 114-11 60C, 205 mg, 21%). Each is identical in all respects except optical rotation with natural samples. For Pandoline (If): IR (KBr): 3500, 3400, 2965, 2800, 1678, 1620 cm- NMR (CDCI3) 8: 0.96 (3H, t), 1.3-1.7 (4H, m), 1.7-2.3 (4H, m), 2.5-2.8 (3H, m), 2.8-3.1 (4H, m), 3.79 (3H, s), 6.8-7.05 (2H, m), 7.15-7.4 (2H, m), 9.05 (1 H, broad) UV(MeOH) nm: 228, 298, 326; MS (m/e) 354 (M+).

Analysis calculated for C2,H26N203 C,71,16;H, 7.39; N, 7.90 found C,70.90;H, 7-35:N,7.78 For epi-pandoline (If'): IR (KBr): 3450 (broad), 3400, 2960, 2805, 1682, 1620 cm- NMR (CDCI3) 8: 0.96 (3H, t), 1.2-2.2 (8H, m), 2.45 (2H, m), 2.5-2.95 (3H, m), 3.05 (1 H, s), 3.1 (1H, d), 3.78 (3H, s), 6.7-7.0 (2H, m), 7.05-7.3 (2H, m), 8.9 (1 H, broad) UV (MeOH) nm: 228, 298, 326; MS (m/e) 354 (M+).

EXAMPLE 7 14-hydroxyvincadifformine lc and 14-hydroxymethyl-e-norvincadifformine ld a) Methyl 2-ethyl-4-oxyranylpentanoate To methyl 2-ethyl-4,5-dehydropentanoate (3.85 g, 27 mmol) in methylene chloride (25 ml) at OOC, was added m-chloroperbenzoic acid (6.5 g, 85%, 32 mmol). The solution was brought to room temperature and stirred for 12 h. The solid which had formed was filtered, washed with methylene chloride and the combined solutions were washed with saturated aqueous sodium carbonate, dried (MgSO4) and concentrated.

Distillation (1 000C, 25 mm) of the crude oil gave the epoxide (3.5 g, 81%).

IR (neat): 2960, 1733, 1192, 1172 cm-1; NMR (CDCl3) d: 0.90 (3H, t), 1.4-2.0 (4H, m), 2.38-2.68 (2H, m), 2,75 ( 1 H, t), 2.95 ( 1 H, m), 3.74 (3H, s).

b) 2-ethyl-4-oxyranylpentanallXc The epoxy-ester (2.08 g, 13.1 mmol) was placed in methylene chloride (20 ml) under nitrogen and cooled to - 780C. With vigorous stirring, diisobutyl aluminum hydride (1.2 equiv., 20% in hexane) was added dropwise over 10 min. The reaction was stirred for an additional 20 min. then quenched with methanol (2 ml) at - 780C. The solution was poured into water and extracted with methylene chloride.

The aluminum salts which formed were separated by gravity filtration through glass wool and were washed with methylene chloride. The combined extracts were dried (MgSO4) and concentrated in vacuo. Distillation (60-65 C, 25 mm) gave 2-ethyl-4-oxyranylpentanal IXc (925 mg, 55%).

IR (neat): 3055, 3023, 2910, 1 720, 1450, 1260 cm- NMR (CDCl3) 8: 1.0 (3H, t), 1.1-2.1 (4H, m), 2.3-2.6 (2H, m), 2.85 (1 H, t), 3.05 (1 H, m), 9.85 (1 H, d).

c) 14-hydroxyvincadifformine Ic and isomer Id Amine Vllla (500 mg, 2.1 mmol) and spoxy-aldehyde lXc (0.5 g, 3.9 mmol) were refluxed under nitrogen in methanol (10 ml) for 2 h. The methanol was removed in vacuo. Compound ld crystallized out after sitting ovemight. lt was crystallized from acetonitrile (503 mg, 68%), mp 153-154 C. The remaining resiclue was purified by preparative TLC (silica gel, 3% methanol in methylene chloride, rf 0.6 for lc and 0.15 of id) yielding a second component (lc) as an amorphous solid (105 mg, 14%).

Fold: IR (KBr): 3260,2950,1682,1605 cm- UV (MeOH) nm: 226, 298,328; MS (m/e) 354 (M+) For Ic: IR (film): 3360 (broad), 2950,2790,1640,1600 cm- UV (MeOH) nm: 228,298,328; MS (m/e) 354 (M+).

EXAMPLE 8 + Pseudo-vincadifformine le and epi- 14 pseudovincadifformine le' a) 4-ethyl-5-hydroxypentanoic acid lactone Methyl 4-formyl hexanoate (15.3 g, 97 mmol) was cooled to 0 C in anhydrous methanol (125 ml) and sodium borohydride (1.84 g, 48 mmol) was added at a rate such that the reaction stayed below 200C. The solution was stirred for 30 min. after the addition was completed and then was extracted with ether (3 x 75 ml). The combined extracts were washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The oil was taken up in benzene (200 ml) and p-toluene-sulfonic acid (1 g) was added. The solution was refluxed for 15h. using a Dean-Stark trap filied with anhydrous calclum chlonide. After cooling the reaction mixture was washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated.Distillation of the crude material gave 4-ethyl-5-hydroxypentanoic acid lactone bp 70-750C (0.25 mm) (7.2 9,58%) IR (neat): 2968,1730,1180,1056 cm- NMR (CDCl3) d: 0.98 (3H, t), 1.2-2.2 (5H, m), 2.58 (2H, m), 4.0 H, H, d of d), 4.35 (1 H, m).

bJ Methyl 4-(bromomethyl)-hexanote Anhydrous HBr gas was bubbled into the 4-ethyl-5-hydroxypentanoic acid lactone (3 g, 23 mmol) at 600C for 30 min. The solution was allowed to cool and methanol (1 5 ml) with trimethylorthoformate (2.5 g, 23 mmol) was added. The solution was stirred for 8 h., then concentrated and distllled bp 70-75 C (0.1 mm) to produce the desired bromester (4.3 g, 83%) lR (neat): 2955,1733,1170 cm- NMR (CDCl3) 8: 0.98 (3H, t), 1.3-2.0 (5H, m), 2.45 (2H, t), 3.6 (2 H, d), 3.82 (3H, s).

c) 4-(bromomethyl)hexanal lXb The above mentioned bromoester (1.9 g, 8.5 mmol) was dissolved in anhydrous methylene chloride (20 ml) and cooled with vigorous stirring to -780C. Diisobutylaluminum hydride (10.2 ml, 1 M in hexane) was added dropwise over 10 min. The solution was stlrred for an additional 20 min. at -78 C and then quenched by the addition of methanol (2 ml). The solution was poured into 3% HCl, extracted with methylene chloride (3 x 30 ml) and dried (MgSO4), Solvent removal gave a light oil which was purified by distillation, bp 78 C (0.4 mm) (1.38 g. 84%).

d) Pseudo vincadifformine le (14-ethyl-18, 19-dinorvincadifformine) and epi-14-pseudovincadifformine /e Azepino-indole VIlla (1.00 g, 4.1 mmol) was dissolved in methanol (30 ml) at room temperature and bromoaldehyde lXb (1.0 g, 5.3 mmol) was added. The solution was stirred for 4 hours at which time, triethylamine (1 ml, excess) was added and the solution was heated at 40 C with stirring for 16 h.

The methanol was removed in vacuo and the residue was taken up in methylene chloride (75 ml), washed with saturated aqueous sodium carbonate, dried (MgSO4) and concentrated. HPLC (using a 10 inch commercial microporacil column with a flow rate of 0.9 ml/min.) eluting with chloroform, showed two components le (retention time: 10.3 min.) and le' (retention time: 8.5 min.) with a ratio of 4:1 which correspond to the two components (ratio 4:1) in a sample of natural pseudo-vincadifformine.

Medium pressure column chromatography (4ft x 1.25 in., silica gel eluting with chloroform allowed isolation of the major isomer as a homogeneous material (by HPLC) which was induced to crystallize by trituration in methanol-water. This was recrystallized from methanol-water (95.5), m.p. 118-11 90C (170 mg, 12%). Enrichment of the remaining mixture of epimers (460 mg, 34%) by selective crystallization produces mixture of no better than a 1:1 ratio.

For Ic: IR (KBr): 3365, 2955, 2773, 1666, 1605, 740 cm- NMR (CDCl3) b: 0.95 (3H, t), 1.1-1.6 (4H, m), 1.6-2.15 (4H, m), 2.15-2.65 (3H, m), 2.65-2.95 (4H, m), 3.68 (3H, s), 6.5-6.7 (2H, m), 6.8-7.2 (2H, m), 8.7 (1 H, broad) UV (methanol) nm: 228, 298, 328.

For a mixture of le and le' (ca 1:1) the NMR spectrum shows a shift of absorbances indicating more protons in the region of 8 1.6-2.5 and fewer in the region of 8 1.1-1.6.

EXAMPLE 9 + 15-chloro, 15-bromo and 15-methoxyvincadifformine Starting from the hydrogenated azepinoindole Vlilc, Vlild, Vlllf obtained respectively from VllC, VIld and Vllf following a procedure similar as for VIlla; these compounds were prepared by the procedure given for vincadifformine in Example 7 of Specification No 2011899. The chloro and bromo products were purified by preparative TLC on Merck silica, developed with 2% methanol in dichloromethane. The bromovincadifformine Ih Rf 0.60 was readily separated from the minor vincadifformine la component Rf 0.48, formed from the contaminating indoloazepine Vllla. The chloro compound, 19 (yield 70%), crystallized from methanol, mp 131-1 320C.

NMR (CCI4): 8.98 (brs, 1 H), 7.02 (m, 2H), 6.71 (d, J = 8Hz 1 H), 3.72 (s, 3H), 3.20-0.80 (brm, 1 5H), 0.64 (+, 3H), IR (CHCl3) vrnax: 3370, 2930, 2770, 1665, 1600, 1465, 1290, 1260, 1150 cm-; UV(MeOH) #max (lg #): 225 (s,4.11), 311(4.20), 338 (4.17), MS(80eV) m/e (rel%) 372 (45), 125 (15), 124 (100).

The bromo compound Ih (yield 45% resisted crystallization, NMR (CCl4)#: 8.94 (brs, 1 H), 7.10 (m, 2H), 6.58 (d, J = 10 Hz, 1 H), 3.64 (s, 3H), 3.20-0.76(brm, 1 5H), 0.60 (t, 3H); lR (CHCl3): 3360, 2930, 2775, 1665, 1600, 1460, 1290, 1260, 1150 cm-; UV (MeOH) A (log #): 225 (sh, 4.11), 310 (4.19), 331 (4.17), MS(80eV) m/e (rel %) 418 (12), 125 (39), 124 (100).

The compound formed a picrate which crystallized from 95% ethanol, mp 203-2040C. The methoxy compound li (yield 60%), was amorphous.

NMR (CDCl3) 8: 8.75 (brs, 1 H), 6.77 (brs, 1 H), 6.62 (m, 2H), 3.73 (s, 3H), 3.71(s, 3H), 3.38-0.80 (m, 1 5H), 0.58 (t, 3H), IR (CHCl3) Pmax: 3380, 2925, 2760, 1660, 1600, 1210, 1140 cm- UV#max (log #): 228 (sh, 4.10), 313 (4.23),331 (4.14). MS(80eV) m/e (M+), 124 (base).

A picrate was recrystallized from 95% ethanol, mp 1 52-1 530C.

EXAMPLE 10 Dimethyl-3-benzyl-9-chloro-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5,5-dicarboxylate (Vle) Following the procedure for preparation of the indoloazepine Vlc, the 9-chloro product Vle mp 111-1 130C was prepared in 60% yield.

NMR (CDCI3) d: 8.49 (s, 1 H), 7.22 (m, 8H), 3.78 (s, 2H), 3.74 (s, 6H), 3.65 (s, 2H), 2.84 (s, 4H); IR (KBr) vmax: 3404,2960,2890,2840, 1725,1455,1430,1320, 1260,1250,1230,1130, 1050,880,803, 802,740,735,695 cm-; UV (ethanol) #max: 239, 295 nm.

Anal. Calcd. for C23H23N204CI: C, 64.71; H, 5.43; N, 6.56; CI, 8.31.

Found: C, 64.71; H, 5.53; N, 6.54; CI, 8.55.

EXAMPLE 11 Dimethyl-3-benzyl-9-bromo-1,2,3,4,5,6-hexahydroaepino(4,5-b)indole-5,5-dicarboxylate(Vle) Following the procedure for preparation of the indoloazepine Vlc, the 9-bromo product Vlf, mp 116-11 80C was prepared in 55% yield.

NMR (CDCI3) : 8.48 (brs, 1H), 7.54 (s, 1 H), 7.25 (s, 5H), 7.14 (s, 2H), 3.77 (s, 2H), 3.72 (s, 6H), 3.62 (s, 2H), 2.81 (s,4H); IR(KBr)vmax: 3440,2950,2905,2815, 1745,1732,1465,1435, 1245,1220,1140,1045, 1025,790,740, 695 cm-; UV (ethanol)#max: 238,293nm.

Anal. Calcd. for C23H23N204 Br: C, 58.60; H, 4.92; N, 5.94; Br, 16.95; Found: C, 58.56; H, 4.86; N, 5.72; Br, 17.10.

Claims

1. A process for the preparation of + vincadifformine or a derivative thereof having the general formula I

wherein each of R, and R2 independently are hydrogen, hydroxy, acyloxy, carbamate, alkoxy, alkyl or halo, R3, R4and R5 independently are hydrogen or C, to C7 alkyl, A represents a saturated or unsaturated carbohydryl chain containing from 1 to 7 carbon atoms which may be substituted by one or more C1 to C7 alkyl, hydroxy or C, to C7 hydroxy-alkyl radicals, which process comprises: a) reacting a tetrahdro-ss-carboline of the formula:

with benzoyl chloride to form a compound of the formula:

wherein # represents a phenyl radical b) reducing the compound of formula Ill by means of a reducing agent to form a compound of the formula::

c) chlorinating the compound of formula IV to form a compound of the formula

d) reacting the compound of formula V with a dialkyl malonate salt at reflux to form a compound of the formula VI wherein R5 = H

which may be, if desired, Na alkylated to give a compound VI wherein R5 is an alkyl group containing from 1 to 7 carbon atoms e) and f) in either order, partially decarboalkoxylating and hydrogenating the compound of formula VI

g) reacting the compound of formula VIII with a functionalised aldehyde able to form an enammonium intermediate with secondary amines, typically a halo or epoxyaldehyde, optionally in the presence of an organic base such as triethylamine to yield the desired vincadifformine derivative of formula I.

2. A process as claimed in claim 1, wherein said reducing agent employed in step b) is lithium aluminium hydride.

3. A process as claimed in claim 1 or claim 2, wherein the chlorination in step e) is effected by use of tertiary butyl hypochlorite in the presence of triethylamine.

4. A process as claimed in any preceding claim, wherein the hydrogenation in step f) is carried out in the presence of a Pd catalyst.

5. A process as claimed in any preceding claim, wherein the dialkyl malonate salt used in step d) is thallium t-butyl methyl malonate.

6. A process as claimed in any one of claims 1 to 4, wherein the dialkyl malonate salt used in step d) is thallium dimethyl malonate.

7. A process as claimed in any preceding claim, wherein the decarboalkoxylation of step e) is effected by treatment using anhydrous trifluoroacetic acid, anhydrous trifluoracetic anhydride or a mixture thereof.

8. A process as claimed in any one of claims 1 to 7, wherein the decarboalkoxylation in step f) is effected by lithium chloride in dimethylformamide.

9. A process as claimed in any preceding claim, wherein said functionalised aldehyde is 1 -bromo 4-formylhexa ne, 4-ethyl-4-oxyra nylpentanal, 2-ethyl-4-oxyranylpentanal, 4-bromomethyl hexanal or 2 ethyl-5-mesyioxypentanal.

1 0. A process as claimed in claim 1 and wherein one or more stages are substantially as hereinbefore described in any one of the Examples.

11. A process for the preparation of a + vincadifformine derivative of formula I as defined in claim 1 which process comprises reacting a compound of the formula VIII as defined in claim 1 with a functionalized aldehyde in a solvent inert to the reaction conditions, optionally in the presence of an organic base, to form the corresponding derivative of formula I.

1 2. A process as claimed in claim 11, wherein the solvent is dry methanol or dry benzene.

13. A process as claimed in claim 11 or claim 12, wherein a catalytic amount of dry triethylamine is added to the solvent.

14. A process as claimed in claim 11, wherein the compound of formula VIII is obtained by, in either order, partially decarboxylating and hydrogenating a compound to the formula VI as defined in claim 1.

1 5. A process as claimed in claim 10 and wherein one or more stages are substantially as hereinbefore described in any one of the Examples.

16. A vincadifformine derivative of formula I as defined in claim 1 produced by a process as claimed in any preceding claim.

17. A process for preparing a dialkyl 3-benzyl- 1 ,2,3,4,5,6-hexahydroazepino-(4,5-b)-indole-5,5- dicarboxylate of the formula:

which comprises chlorinating 2-benzyl-1,2,3,4,-tetrahydro-9H-pyrido(3,4-b)-indole of the formula:

with t-butyl hypochlorite under cooling in the presence of dry triethylamine to form a chloroindolenine of the formula:

and immediately reacting said chloroindolenine (formuia V) with a dialkyl malonate salt.

18. A process as claimed in claim 17, wherein one or more steps are substantially as specifically described in any one of the Examples.

19. A compound of the formula VI as defined in claim 17 when prepared by a method claimed in claim 1 6 or claim 17.

20. As new intermediate compounds those of the formula

wherein R, and R2 are hydrogen, hydroxy, acyloxy, carbamate, alkoxy, alkyl or halo or combination of such substituents; R5 represents hydrogen or an alkyl group having 1 to 7 carbon atoms; R represents hydrogen or benzyl; one of R, and R5 may represent hydrogen or carboalkoxy or both R7 and R5 may represent carboalkoxy wherein the alkoxy group has 1 to 4 carbon atoms and may be different from one another.

21. Dimethyl 3-benzyl 1 ,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5,5-dicarboxylate.

22. Dimethyl 1 ,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5,5-dicarboxylate.

23.Dimethyl-8-methoxy 1,2,3,4,5,6-hexahydroazepino94,5-b)indole-5,5-dicarboxylate.

24.Methyl-8-methoxy 1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5-carboxylate.

25. Methyl 9-methoxy 1 ,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5-carboxylate.

26. Methyl 9-ch loro 1 2,3,4,5,6-hexa hyd roazepino(4,5-b)indole-5-carboxylate.

27.Methyl 9-bromo 1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5-carboxylate.

28. A compound of any one of formula Ixb to Ixf as hereinbefore defined.

29. A method for preparing a compound of the formula Ixd substantially as hereinbefore described.

30. A method for the preparation of 5-bromo-2-ethyl pentanal comprising acetalising methyl or ethyl 4-formyl hexanoate, reducing the methyl 4-dimethoxymethyl hexanoate or ethyl 4-diethoxymethyl hexanoate so produced with lithium aluminium hydride and dehydroxybrominating the 4dimethoxymethyl-1-hexanol or4-diethoxymethyl-1 -hexanol so produced and hydrolysing the resulting 1 -bromo-4-dimethoxymethyl hexane or 1 -bromo-4-diethoxymethyl hexane to 5-bromo-2-ethyl pentanal.

31. A process for preparing an intermediate compound comprising one or more of step (a), step (b), step (c), step (d), step (e) or step (f) as defined in claim 1.