Title of Invention

PROCESSES FOR THE PREPARATION OF COMBRETASTATINS

Abstract

ABSTRACT METHOD FOR PREPARING COMBRETASTATINS This invention concerns novel methods for preparing combretastatins by Witting condensation between nitromethoxy-benzaldehyde and a trimethoxybenzyl phosphonium salt or inversely a nltromethoxybenzyl phosphonium salt with trimethoxybenzylaldehyde or further by a Witting reaction on the same derivatives whereof the nitro function has been reduced into an amino group.

Full Text

PROCESSES FOR THE PREPARATION OF COMBRETASTATINS The present invention relates to a novel process for the preparation of combretastatins and of their derivatives. The term "combretastatins" or "stilbene derivatives" is understood to mean the derivatives of group, and its pharmaceutically acceptable salts. Mention may be made, among the salts, of the hydrochloride, acetate, phosphate or methanesulphonate. When the compound A is an amino group, it can also be coupled to amino acids to result in amides, and their pharmaceutically acceptable salts. The synthesis of stilbene derivatives or combretastatins, which can be in the form of a pharmaceutical acceptable salt, and the pharmaceutical compositions which comprise them are disclosed in Patents US 4 996 237, US 5 525 632, US 5 731 353 and US 5 674 906. These patents disclose combretastatins and their metabolites and disclose their in vitro oncologic activity. According to these patents, combretastatins are prepared from (3,4,5-trimethoxybenzyl)triphenyl-phosphonium salts, which is condensed with a 3-nitro- or 3-hydroxy-4-methoxybenzaldehyde (the hydroxyl group of which is protected) in the presence of sodium hydride or of lithium derivatives, and then the derivative obtained, when it is nitrated, is reduced in the presence of zinc. The isomer with the cis configuration is subsequently prepared by the action of light or by chromatographic separation of the mixture. The present invention relates to novel processes for the preparation of combretastatins or of their derivatives and to improvements to the existing processes. A first process route VO 1 for the preparation of derivatives of formula (I) for which A represents an amino group has first been discovered, which process is an improvement to the process disclosed in the abovementioned patents, which consists, after the Wittig condensation in the presence of (3,4,5-trimethoxyben2yl)triphenylphosphonium bromide or chloride and of 3-nitro-4-methoxybenzaldehyde, in carrying out the reduction in the presence of iron, instead of the zinc used in the prior publications, which makes it possible to achieve an overall reaction yield, with respect to the aldehyde charged, of 60% (the yield with respect to the aldehyde charged in Patent US 5 525 632 is between 21% to 33%) . The first process route VO 2 consists in condensing 3,4,5-trimethoxybenzaldehyde with (4-methoxy-3-nitrobenzyl)triphenylphosphonium bromide or chloride. For both these first two processes routes VO 1 and VO 2, the reaction is carried out in the presence of a base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA (lithium diisopropylamine) , sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilanes. This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will be adjusted by a person skilled in the art to the base used and to the solvent used. This reaction, as regards the first process route VO 2, is described in particular in the publication by K.G. Piney which appeared in Bioorg. Med. Chem., 8(2000), 2417-2425. 2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)-vinyl]nitrophenyl is reduced according to the improved process of the invention by the action of iron. It is advantageous to use an amount of iron in excess if complete conversion of the starting material is desired. This excess is advantageously greater than 2 equivalents per one mol of starting nitro derivative. It has been shown that the same stage, carried out in the presence of zinc in acetic acid, a conventional solvent for reductions with zinc, does not make it possible to obtain complete reaction (in Patent US 5 525 632, the yield of the reduction carried out on the pure 2 isomer varies between 46 and 66%) and, moreover, the amounts of zinc used are large and consequently result in considerable industrial waste. Furthermore, the process generates a large amount of "azo" compound resulting from coupling between the amino formed and the nitroso intermediate in the reduction. Reduction with nascent hydrogen, generated by ammonium formace in the presence of a conventional catalyst, such as palladium or platinum, leads to high isomerization of the double bond to the undesirable E isomer and to partial saturation of the double bond. The abovementioned Piney publication describes the reduction by sodium hydrosulphite of a pure nitro 2 isomer, obtained after chromatography and recrystallization, leading to an amino Z isomer with a yield of only 37%. Hydrogenations with molecular hydrogen, catalysed by platinum or palladium, are rarely complete and result in particular in the saturation of the ethylenic double bond. A second process has also been found which avoids the intermediate reduction stage necessary when starting from a nitro derivative. This is because it is much more economical to condense, according to a first nethod of carrying out this second process, a [3,4,5-trimethoxybenzyl)triphenylphosphonium bromide or chloride with a 3-amino-4-methoxybenzaldehyde or, iccording to a second method of carrying out this second process, 3,4,5-trimethoxybenzaldehyde with a (3-amino-4-methoxyben2yl)triphenylphosphonium salt. This second process according to its two alternative forms requires a stage in which less in the way of CMR (Caneerogenic. Mutagenic or Reproductive toxic) products are given off in comparison with the first processes routes VO 1 and VO 2, which is a considerable advantage at the industrial level from the viewpoint of safety and production cost. According to the second process route VO 3 for implementing the invention, the (3,4,5-trimethoxybenzyl)triphenylphosphonium salt and 3-amino-4-methoxyben2aldehyde are brought together and the reaction is carried out, preferably, in the presence of a base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA, sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilanes. Use is preferably made of sodium methoxide. This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will be adjusted by a person skilled in the art to the base used and to the solvent used. The reaction temperature will be adjusted by a person skilled in the art to the base used. When methoxide is used, it is preferably between 0 and 10°C. After reaction, the base used is neutralized with an acid in aqueous solution, the organic phase is washed and concentrated, and the expected product is obtained after chroraatographing the crude concentrate. According to the second process route VO 4 for implementing the invention, in which the (3-amino-4-methoxybenzyl)triphenylphosphonium salt and 3,4,5-trimethoxybenzaldehyde are brought together, the reaction is preferably carried out in the presence of an organic base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA, sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilanes. Use is preferably made of sodium methoxide. This reaction is carried out in various solvents, such as ethers (THFl, polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will be adjusted by a person skilled in the art to the base used and to the solvent used. The reaction temperature will be adjusted by a person skilled in the art to the base used. When methoxide is used, it is preferably between 0 and 10°C. After reaction, the base used is neutralized with an acid in aqueous solution, the organic phase is washed and concentrated, and the expected product is obtained after chromatographing the crude concentrate. The derivative obtained according to the second process route VO 3 or VO 4 or during the second stage of the first process route VO 1 or VO 2 has the couple serine with the compound of formula (Ila), to use L-serine doubly protected on the nitrogen of the serine and on che hydroxyl functional group of general functional group known to any person skilled in the art, to give a novel intermediate of following general simultaneously with the opening of the ring, by acid hydrolysis according to a deprotection reaction known to any person skilled in the art. Preferably, the PG group of the formulae (lib) or (III) represents a protective group chosen from the following groups: tert-butoxycarbonyl, benzyloxycarbonyl (CBZ) or 9-fluorenylmethyloxycarbonyl (FMOC). The compound of formula (III) above is novel and is claimed as such. The condensation is advantageously carried out in the presence of EDCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide chloride) or in the presence of DCC (dicyclohexylcarbodiimide) and of HOBT (hydroxybenzotriazole) or in the presence of DCC (dicyclohexylcarbodiimide) and of HOSU (N-hydroxysuccinimide) or, finally, in the presence of TOTU (0-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate) or of HBTU (0-benzotriazol-l-yl-N,N,W,N'-tetramethyluronium hexafluorophosphatel or of N,N-carbonyldiimidazole. The reaction is preferably carried out in a solvent which is inert with respect to the reaction, which solvent is chosen in particular from polar aprotic solvents, such as acetonitrile, dimethylformamide, tetrahydrofuran or chlorinated aliphatic solvents, such as dichloromethane, or, finally, esters. The coupling to the derivative of formula (Ila) can also certainly be carried out by the action of a mixed anhydride, synthesized in situ between a chloroformate or a carboxylic acid chloride, for example pivaloyl chloride, and doubly protected L-serine of formula (lib), in the presence of a tertiary base of the NMM (N-methylmorpholine) type in various solvents which are inert with respect to the reaction, esters, ethers, chlorinated solvents, acetonitrile, and the like. The mixed anhydride is preferably prepared at a temperature of between 0 and 10°C and then the reaction is carried out at ambient temperature. After reaction, the reaction mixture is hydrolysed with an aqueous solution, then the mixture is separated by settling and the organic phase obtained is washed with a hydroxylated base. The double deprotection of the compound of formula (III) is carried out by the action of an organic or inorganic acid. Use is preferably made of concentrated aqueous hydrochloric acid in an alcoholic medium. The reaction temperature is, according to a better means of implementation of the invention, between 50 and 70°C. The invention will be more fully described with the help of the following examples, which must not be regarded as limiting the invention. The composition of the mixtures, the monitoring and the progression of the reactions, and the yield of the unisolated products/intermediates and their assays are determined by HPLC (High Performance Liquid Chromatography) analysis. Example 1 - First process route VO 2 according to the invention (Z)-N-[2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]- phenyl]-L-serinamide hydrochloride General scheme of the synthesis The novel "inverse Wittig" process, starting from (4-methoxy-3-nitrobenzyl)triphenylphosphonium bromide and 3,4,5-trimethoxybenzaldehyde, makes it possible to obtain the mixture of Z and E isomers of This ratio is sufficiently high in the Z nitro isomer to be able to use the Z/E mixture directly in the reduction and to obtain, by crystallization of the hydrochloride, the Z amino isomer with an HPLC assay of 97% IS [internal standardization). (4-Methoxy-3-nitrobenzyl) triphenylphosphonixom bromide (4) is prepared according to the following 90.5 g of 3-nitro-4-inethoxybenzaldehyde (1) are charged, followed by 450 ml of THF and 90 ml of ethanol, to a 2-litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid and a reflux condenser surmounted by a bubble counter. The pale-yellow solution obtained is cooled to 10°C and then 10 g of sodium borohydride are charged over 40 minutes at 10/15°C {the reaction is very exothermic and the temperature has to be maintained with an ice/acetone bath); at the end of the addition, the brown solution turns navy blue. The solution is stirred for 30 minutes at 10°C, the end of the reaction is monitored by TLC (thin layer chromatography), the solution is stirred for a further 1 hour at 10°C and then the temperature is allowed to return to ambient temperature. The addition funnel is replaced by a 500 ml pressure-equalizing dropping funnel, via which 3Q0 ml of distilled water are run in dropwise over 30 minutes while maintaining the mixture at 20°C. Gas evolution is observed when the water begins to be run in. The mixture is concentrated to 2/3 on a rotary evaporator (50'C/20 mmHg) and a white product crystallizes in the aqueous concentrate in the form of lumps. The cooled aqueous phase is extracted with 250 ml and then 150 ml of dichloromethane, and the combined organic phases are washed with 250 ml of distilled water and then dried over magnesium sulphate. After filtration, the dichlororaethylene solution is used as is in the following bromination reaction. The yield of this stage is regarded as being 100%. N.B.: The alcohol (2} is commercially available but very difficult to get hold of. 3-Nitro-4-methoxybro!nobenzyl (3) : The dichloromethylene solution of 3-nitro-4-methoxybenzyl alcohol (2) is charged to a 1 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a dropping funnel and a reflux condenser surmounted by a bubble counter, and 100 ml of dichloromethane are added. The stirred solution is cooled to 5°C and then 135.4 g of phosphorus tribromide are run in dropwise while maintaining the temperature at 5°C. The solution is stirred at 5°C for 1 hour 30 minutes, the end of the reaction is monitored by TLC and then 250 ml of saturated sodium hydrogencarbonate solution are run in dropwise while maintaining the temperature at 15°C. Very strong evolution of gas takes place with a slight delay as the phosphorus tribromide is run in. The medium, separated by settling in a separating funnel, is washed successively with 250 ml of distilled water and 200 ml of saturated sodium hydrogencarbonate solution. The organic phase is dried over raagnesium sulphate, filtered and concentrated on a rotary evaporator (50°C/20 mmHg). 119 g of solid in the form of green-yellow felt-like needles are obtained with a chemical yield over two stages of 97%. N.B.: This product (3) can also be prepared according to the following scheme, described in the publication: 119 g of 3-nitro-4-methoxybromobenzyl (3) are charged to a stirred heel of 1 000 ml of toluene in a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid and a reflux condenser surmounted by a bubble counter, and the mixture, warmed to 25°C, passes into solution. 126.5 g of triphenylphosphine are then added and the solution obtained is gradually heated to 60°C; a precipitate is formed from 30'=C. The mixture is maintained at 50/65°C for 4 hours, is then cooled to 30°C and is filtered through a sintered glass filter. The filter residue is washed on the filter with 2 times 300 ml of toluene, pulled dry and dried in an oven (35°C/20 iTimHg/2a hours). 217 g of (4-methoxy-3-nitrobenzyl)triphenyl-phosphonium bromide are obtained with a chemical yield of 88%. Synthesis described in the publication: (solvent used: dichloromethane) K.G. Piney et al., Bioorg. Med. Chem., 8(2000), 2417-2425. Spectrum No. = 4 865-V H K.M.R. spectrum (300 MHz, dg-(CD3)2SO, S in ppm): 3.90 (s, 3H), 5.26 (d, J = 15 Hz, 2H), 7.33 [mt, 2H), 7.41 (mt, IH), from 7.65 to 8.05 (mt, 15H). Mass spectrum No. 212217, m 428 EI m/z = 262 [PPhj]' base peak DCI m/z = 445 MNH3' m/z = 428 M* m/z - 263 [PPhsH] base peak IR spectrum 426469 KBr 2869, 2843, 2776, 1619, 1527, 1438, 1362, 1287, 1270, 1111, 752, 692 and 502 cm-1 Z and E mixture of 2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)vinyl]nitrophenyl (6) and (7): charged, at 2 0°C and under nitrogen, to a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a dropping funnel and a reflux condenser surmounted by a bubble counter. The stirred suspension is cooled to 5°C using an ice bath and then 63.2 g of a 25% w/w solution of sodium methoxide in methanol are run in at 5°C over 40 minutes. As the addition progresses, the suspension changes from off-white to yellow and then to brown. The mixture is stirred for 1 hour at 5°C and the end of the reaction is monitored by HPLC {complete consumption of the aldehyde). 3 g {0.05 mol) of acetic acid are then added. The suspension is heated to 40°C and is maintained at 40*0 for 30 minutes. At this temperature, only the salts remain insoluble. The mixture is filtered at 40°C through a sintered glass filter JMo. 3 and the salts are washed on the filter with 3 times 100 ml of toluene. The filtrate is returned to a round-bottomed flask with 250 ml of distilled water, and the two-phase mixture is stirred for 20 minutes at 40*0 and then separated by settling in a separating funnel. The toluene phase is washed again with 2 times 250 ml of distilled water and then concentrated to dryness on a rotary evaporator. The residue is taken up in 600 ml of isopropanol and 12 ml of toluene at 40°C, the expected product begins to crystallize and the temperature is allowed to return to ambient temperature overnight with slow stirring. The stirred suspension is cooled to and maintained for 1 hour at 5°C and then filtered through a sintered glass filter, and the cake is washed with 2 times 125 ml of isopropanol, pulled dry and dried in an oven under vacuum (35°C/30 mmHg/18 hours). 91.7 g of a mixture of Z and E isomers (6) and (71 are obtained with a Z/E ratio of 75/25 (IS HPLC} and a yield of 95%. Synthesis described in publication: (solvent used: dichloromethane: base used: NaH) K.G. Piney et al., Bioorg. Med. Chem., 8(2000), 2417-2425. N.B.: Numerous operating conditions were experimented with, such as: Solvents: THF, acetonitrile, methanol and other alcohols, dichloromethane, NMP, DMF, DMSO, and the like. Bases: potassium t-butoxide, sodium C-pentoxide, sodium hydroxide, NaH, BuLi/LDA, potassium carbonate and the like. Temperatures: from -10°C to the reflux temperatures of (6) and (7), 640 ml of absolute ethanol and 160 ml of distilled water are charged, at 20°C and under nitrogen, to a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid, a reflux condenser surmounted by a bubble counter, and a heating bath. The mixture is rapidly stirred and heated on an oil bath, 7.8 ml of 5N hydrochloric acid are a 52 g of iron powder are added portionwige over 5 minutes. With the first addition, the mixture passes into solution and then a blackish deposit is formed on the walls of the round-bottomed flask. The mixture is maintained at 77 ± 2°C for 2 hours and the disappearance of the starting nitro compounds (6) and (7) is monitored by HPLC. The mixture is allowed to cool to 40°C and is filtered through a sintered glass filter covered with clarcel and the cake is rinsed with 2 times 160 ml of 80/20 ethanol/water mixture. The filtrate, aqueous mother liquors and aqueous wash liquors, is concentrated on a rotary evaporator. As soon as the azeotrope has been driven off, an oil begins to precipitate in the residual aqueous phase. This aqueous phase is extracted in a separating funnel with 2 times 3 00 ml of dichloromethane and then the organic phase is washed with 2 times 300 ml of half-saturated aqueous sodium chloride solution and with 300 ml of distilled water. The organic phase is concentrated to dryness on a rotary evaporator and 7 5 g of an oil are obtained, which oil exhibits a Z/E ratio of 80/20 by HPLC. This oil is dissolved in 591 ml of methanol and transferred into a stirred 1 litre round-bottomed flask, 100 ml of 2.32N methanolic hydrochloric acid are then added, precipitation is initiated and the mixture is allowed to precipitate overnight with stirring. The amount of methanol + methanolic hydrochloric acid is such that the final concentration of Z isomer (determined by HPLC} is equal to 8.8% w/v. In the morning, the mixture is filtered through a sintered glass filter. The dried cake weighs 8.2 g and is composed only of E isomer (HPLC). The filtrate (693 g), ratio Z/E = 86/14 ' (IS HPLC), is concentrated to half on a rotary evaporator, 400 ml of acetonitrile are added Co the 347 g of concentrate and the mixture is reconcentrated until a concentrate of 347 g is again obtained. 1 000 ml of acetonitrile are then added and the mixture is concentrated until crystallization begins. The concentrate is then transferred into a stirred 4 litre round-bottomed flask containing 1 500 ml of acetonitrile at 60°C. The mixture copiously precipitates. The mixture is kept stirred at 60°C for 2.5 hours and is allowed to cool to 30°C over approximately 1 hour. The slurry is filtered through a sintered glass filter (the E isomer (9) is soluble in the filtrate). The cake is washed with 2 times 200 ml of acetonitrile and dried in an oven (35°C/30 mmHg/ 18 hours). 45.7 g of Z-2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)vinyl]phenylamine (8) are obtained with an IS HPLC assay of 97% and a yield as such of 56%, i.e. a yield of 2 isomer obtained with respect to Z isomer charged of 72%. EXAMPLE 2 - Synthesis according to the second process route VO 3 according to the invention The advantage of the second process route VO 3 with respect to the first "inverse Wittig" process route VO 2 is that of carrying out the Wittig reaction between a product which has already been reduced, the aminoaldehyde (la), and the phosphonium (2a) and thus of eliminating a chemical stage which gives off CMR products. (Z)-N-[2-MethQxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenyl]-L-serinamide hydrochloride three-necked flask rendered inert with argon and equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid, a reflux condenser surmounted by a bubble counter, and a heating bath, and the mixture is stirred and heated to 60°C. The mixture passes into solution. The dropwise addition is carried out at 60°C of 115 ml of distilled water, followed by 14 ml of 2N hydrochloric acid. 24.7 g of iron powder are then introduced portionwise. The temperature of the mixture is allowed to return to ambient temperature over 2 hours. The reaction is complete (TLC). The mixture is filtered through celite and concentrated under vacuum, the residue is taken up in dichloromethane and the organic solution is washed twice with distilled water and then dried over magnesium sulphate, filtered and concentrated to dryness under vacuum. 16 g of crude (la) are obtained and are chromatographed on a silica column eluted with dichloromethane. 2 fractions comprising the clean expected product are obtained, which fractions, after concentrating, give 11.5 g of pure (la), i.e. a yield of 69%. -H N.M.R. spectrum No. 2810-V {300 MHz, d6-{CD3)2SO, 5 in ppm): 3.88 (s, 3H), 5.11 (unresolved peak, 2H), 7.01 (d, J = 8 Hz, IH), 7.14 (d, J = 2 Hz, IH), 7.18 (d, J - 8 Hz, IH) , 9.53 [s, IH) . Mass spectrum No. 210112, m - 151 EI m/z = 151 M"- base peak m/z = 136 [M-CH3]" m/z = 108 [136-CO] m/z = 80 [108-CO]* IR spectrum: 425135 KBr 3464, 3437, 3367, 3349, 1675, 1655, 1582, 1513, 1293, 1241, 1139, 1023, 803 and 640 cm-1* already disclosed in the original patent Ajinomoto Co. Ltd, US 5 525 632 and WO 01/12579 A2 . 8.0 g of phosphonium salt (2a), followed by 2.20 g of aminobenzaldehyde (la) and 100 ml of toluene, are charged to a 250 ml three-necked flask rendered inert with nitrogen and equipped with a magnetic stirrer, a thermometer, a T piece, a dropping funnel, a reflux condenser surmounted by a bubble counter, and a cooling bath. The stirred suspension is cooled to 5°C and 3.51 ml of a 25% w/w methanolic sodium methoxide solution are run in over 15 minutes. After 2.5 hours at 5°C, the reaction remains incomplete (DC: 45%) but does not change further (HPLC) and the Z/E ratio is 61/39. 0.2 ml of acetic acid diluted in 50 ml of water is then run in, the temperature rises to 13°C, the mixture is stirred for 3 0 minutes and then it is separated by settling in a separating funnel. The organic phase is concentrated under vacuum on a rotary evaporator and 8 g of yellow oil are obtained. By HPLC, this oil comprises starting aldehyde, phosphine oxide and the expected Z/E mixture with a ratio of 61/39. The oil is chromatographed on a silica column (40 parts w/w> eluted with a cyclohexane/ethyl acetate/ triethylamine (50/50/2) mixture. 2 series of combined fractions are concentrated to dryness: the first dry extract of 360 mg comprises 93% of the Z isomer + unidentified impurities; the second, of 2.09 g, comprises starting aldehyde and a Z/E mixture representing 39 and 37.5% by IS HPLC. The balance by weight of Z isomer (8M-determined by IS HPLC, is 1.15 g with respect to 2.20 g of aldehyde charge, i.e. a yield of 24%. EXAMPLE 3 - Synthesis according to the second process route VO 3 according to the invention As for route VO 2, the advantage of route VO 3 with respect to the first "inverse Wittig" process route VO 2 is that of carrying out the Wittig reaction between a product which has already been reduced, [3-amino-4-methoxybenzyl)triphenylphosphonium bromide (lb), and 3,4,5-trimethoxybenzaldehyde (5) and thus of eliminating a chemical stage which gives off CMR products. distilled water are charged to a 1 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid, a reflux condenser surmounted by a bubble counter, and a heating bath. 1.76 ml of 6W hydrochloric acid are added to the stirred suspension, which is heated to 70°C. 9.9 g of iron powder are then added portionwise over 15 minutes; the mixture remains insoluble. The mixture is maintained at 75'C for 2 hours; the organic materials slowly pass into solution while a brownish deposit of iron and of iron oxide is formed. After monitoring by HPLC, 5% of starting material still remains; 2 g of iron are again added and heating is continued for 1 hour; the DC is complete. The mixture is cooled to 40°C and filtered through clarcel, the filter residue is rinsed with 100 ml of ethanol comprising 20% water, and the filtrate is concentrated to dryness under vacuum on a rotary evaporator. The residue is taken up in 300 ml of isopropanol and crystallizes from the mixture, which is stirred and heated to 50°C and passes back into solution. 14 ml of a 5N solution of hydrochloric acid in isopropanol are then run in, the mixture precipitates, it is held at 50°C for 1 hour and then it is allowed to return to ambient temperature. The slurry is filtered through a sintered glass filter and the cake is washed with 50 ml of isopropanol, pulled dry thoroughly and dried in an oven under vacuum. 27.3 g of {lb) are obtained with a yield as such of 89.9%. H N.M.R. spectrum No. 4584-V {300 MHz, d6-(CD3)2SO, 5 in ppm): 3.78 (s, 3H), 5.03 [broad d, J - 15 Hz, 2H), 6.43 (unresolved peak, 1H>, 6.62 [broad s, 1H>, 6.82 [broad d, J - 8 Hz, IH), from 7.60 to 8.00 [mt, 15H). Mass spectrum No. 211915, m - 397 EI m/z - 397 M' m/z 382 [M-CH3]* m/z = 262 [PPh;] base peak DCI m/z = 398 MNH M/z = 263 [PPh.Hl" base peak IR spectrum 426386 KBr 3254, 2474, 1920, 1528, 1520, 1439, 1433, 1279, 1110, 736, 690, 527 and 511 cm-1 Z- and E-2-Methoxy-5-[2-[3,4,5-trimethoxyphenyl)vinyl]-phenylamine (8'} and O'): toluene are charged to a 250 ml three-necked flask rendered inert with nitrogen and equipped with a magnetic stirrer, a thermometer, a T piece, a dropping funnel, a reflux condenser surmounted by a bubble counter, and a cooling bath. The stirred suspension is cooled to 5°C and 4.92 ml of a 2 5% w/w solution of sodium methoxide in methanol are run in over 15 minutes. The suspension is stirred at 5°C for 2.5 hours, then 0.2 ml of acetic acid diluted in 50 ml of water is then run in, the temperature rises to 14°C and the mixture becomes very-thick. It is diluted with 10 ml of toluene and 10 ml of water. A brown insoluble material remains. The mixture is filtered through clarcel, the cake is washed with 3 times 50 ml of toluene (the wash liquors comprise virtually only the starting aldehyde and are not added to the two-phase filtrate), the clear filtrate (pH 12) is separated by settling in a separating funnel, and the organic phase is concentrated to dryness under vacuum at AO°C. The 2/E ratio, determined by IS HPLC, is 43/57. The brown oil obtained (4 g) is cnroraatograpfted on a silica column [100 parts w/w) eluted with a cyclohexane/ethyl acetate/triethylamine (50/50/2) mixture. Two series of coinbined fractions are concentrated to dryness: the first dry extract of 1.1 g comprises 14% of E isomer and 59% of Z isomer; the second weighs 1.08 g and comprises 85% of E isomer and 7% of Z isomer. The balance by weight of Z isomer {8'), determined by IS HPLC, is 0.725 g with respect to 4 g of aldehyde charged, i.e. a yield as such of 11.3%. Z-4-{2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-phenylcarbamoyl}-2,2-dimethyloxazolidine-3-carboxylic 44 g of (8), 16 g of sodium hydrogencarbonate and then 200 ml of distilled water and 375 ml of dichloromethane are charged to a 1 litre Erlenraeyer flask. The mixture is stirred for 20 minutes at ambient temperature and two clear phases are obtained. The organic phase is separated by settling, dried over sodium sulphate and then filtered. Approximately 400 ml of a dichloromethane solution comprising (8') are obtained. Preparation of 2,2-dimethyloxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (10) Although commercially available, this product is very difficult to get hold of. It has therefore been prepared by saponification with lithium hydroxide of its methyl ester according to: J. Org. Chem., 53(12), p. 3983 (1998). H N.M.R. spectrxim (300 MHz, d6-(CD3)2SO, 6 in ppm) : 1.38 (s, 3H), 1.45 (s, 9H), 1.55 [s, 3H), 3.95 (mt, IH), 4.16 (mt, IH), 4.31 (mt, IH), from 12.50 to 13.10 (broad unresolved peak, IH). Mass spectrum: No. 213135, ra = 245 DCI m/2 = 263 KNH4 m/z = 246 MH* m/z = 207 [MNH4-t-Bu]"' base peak m/z 146 [MH-BOC]* IR spectrum: 426759 KBr 1744, 1704, 1638, 1407, 1368, 1164, 1104, 856, 836 and 623 cm-1 Coupling: The solution of (8') is charged to a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a funnel for the addition of solid, a reflux condenser surmounted by a bubble counter, and an ice bath, 600 ml of dichloromethane are added and the mixture is cooled with stirring. 42.9 g of 2,2-dimethyloxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (10) are added at 5°C and pass into solution, and then 48 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) are added portionwise between 5 and 10°C. The mixture is slowly allowed to return to ambient temperature by allowing the ice in the bath to melt overnight. In the morning, 330 ml of distilled water are added and the mixture is vigorously stirred. The mixture turns cloudy over 30 minutes (hydrolysis of the EDCl). Stirring is maintained for a further 30 minutes. The mixture is separated by settling in a separating funnel and the organic phase is washed successively with 2 times 280 ml of 0.55N sodium hydroxide solution and then with 300 ml of distilled water. The organic phase is concentrated to dryness on a rotary evaporator (50°C/50 mmHg). 79.4 g of a sticky oil (11} are obtained, which oil hardens at 20°C, with a yield by weight with respect to (8) charged of 117%. Spectrum No. 5 578-V H N.M.R. spectrum (400 MHz, d6-{CD3)2SO, at a temperature of 373 K, 5 in ppm): 1.41 (s, 9H), 1.53 (s, 3H), 1.64 (s, 3H), 3.64 (s, 6H), 3.71 (s, 3H), 3.96 (s, 3H), 3.99 (dd, J = 9 and 3 Hz, IH), 4.19 [dd, J = 9 and 7 Hz, IH), 4.52 (dd, J = 7 and 3 Hz, IH), 6.48 (d, j = 12.5 Hz, IH), 6.55 (d, J = 12.5 Hz, IH), 6.58 (s, 2H), 7.02 (mt, 2H), 8.13 (broad s, IH), 8.82 (broad s, IH). Mass spectrum No. 213565, m = 542 DCI m/z = 560 MNH/ base peak m/z - 543 MH* m/z - 504 [MNH4-t-Bu]" m/z = 443 [MH-BOC]' IR spectrum: 425857 CCI4 3409, 2982, 2938, 2837, 1712, 1698, 1534, 1363, 1249, 1133, 1092 and 851 cm-1 Other coupling conditions were employed, such as: - Mixed anhydride (pivaloyl chloride/{10)). - DCC/HOBT, DCC/HOSU, TOTU, N,W-carbonyldiimidazole, and the like. - In acetonitrile, DMF, THF, dichloromethane, ester, and the like. EDCl-HCl in dichloromethane gave the best methanol, are charged at 20°C to a 1 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a reflux condenser surmounted by a bubble counter, and a heating bath, and 150 ml of isopropyl acetate, 99 ml of a 2.3N solution of hydrochloric acid in methanol and 8.2 ml of distilled water are added. The mixture is stirred and heated at 60°C for 3 hours. The solution, cooled to 40°C, is clarified by filtration through a sintered glass filter No. 4 rinsed with 40 ml of methanol. The filtrate is returned to the stirred three-necked flask and 194 ml of isopropyl acetate are added, the mixture is reheated to 40°C, the solution is initiated with 0.2 g of (12) and then 194 ml of isopropyl acetate are run in dropwise over 1 hour. The mixture slowly crystallizes as the isopropyl acetate is being run in. The mixture is allowed to return to ambient temperature and is then cooled to and maintained overnight at 5°C. In the morning, the slurry is filtered through a sintered glass filter and the cake, pulled dry, is washed with 4 times 50 ml of isopropyl acetate, pulled dry thoroughly and then dried in an oven to constant weight (35°C/10 mmHg). 28 g of (12) are obtained with a yield over 2 stages (coupling and then deprotection operations) of: 56%, and an IS HPLC assay > 98%, i.e. an overall yield as such, for the synthesis carried out according to the first process route VO 2, of: 30% [(12) obtained with respect to (5) charged]. We claim, 1. Process for the preparation of combretastatlns of following general formula(1): In which A represents an amino group, characterized In that, after the Witting condensation In the presence of (3,4,5-trimethoxybenzyl) trlphenylphoshonlum bromide or chloride and of 3-nltro-4-methoxybenzaldehyde or of 3,4,5-trlmethoxybenzaldehyde with a (4-methoxy-3-nltrobenzyl) triphenylphosphonlum salt, the nitro group is reduced in the presence of Iron. 2. The process as claimed In claim 1, wherein that the amount of Iron used Is In excess- 3. The process as claimed In Claim 2, wherein that this excess Is greater than 2 equivalents per one mol of starting nitro dertvative,

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