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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
  • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
  • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
  • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a new process for the preparation of combretastatins and their derivatives.
• Combretastatins or derivatives of stilbene are understood to mean the derivatives of the following general formula:
• A represents a hydroxyl group or an amino group as well as its pharmaceutically acceptable salts.
• the compound or A is an amino group it can also be coupled to amino acids to lead to amides as well as their pharmaceutically acceptable salts.
• the combretastatins are prepared from (3,4,5-trimethoxy-benzyl) -triphenylphosphonium salts which are condensed on a 3-nitro or 3-hydroxy (whose hydroxyl group is protected) 4-methoxy benzaldehyde presence of sodium hydride or lithiated derivatives then the derivative obtained, when it is nitrated is reduced in the presence of zinc.
• the cis configuration isomer is then prepared by the action of light or by chromatographic separation of the mixture.
• the present invention relates to new methods of preparing combretastatins or their derivatives as well as improvements to existing methods. It was first discovered a first process route V0 1 for the preparation of derivatives of formula (I) for which A represents an amino group, which is an improvement to the process described in the patents cited above which consists, after the Wittig condensation in the presence of bromide or (3,4,5-trimethoxy-benzyl) -triphenylphosphonium chloride and 3-nitro 4-methoxy benzaldehyde, to carry out the reduction in the presence of iron, instead of the zinc used in the prior art, which makes it possible to reach an overall yield of the reaction, relative to the aldehyde engaged, of 60% (the yield relative to. aldehyde engaged in US patent 5,525,632 is between 21% to 33%).
• the first Way V0 2 process consists in condensing 3,4,5-trimethoxy-benzaldehyde with bromide or (4-methoxy-3-nitro-benzyl) -triphenylphosphonium chloride.
• V0 1 and V0 2 the operation is carried out in the presence of a base chosen from, in particular, potassium terbutylate, sodium teramylate, sodium mydride, butyllithium, LDA (Lithium diisopropylamine), methylate sodium, 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, DMSQ), alcohols, aromatic solvents or. Water, at a temperature which will be adapted by man. of wax at the base used and at the solvent used.
• solvents such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSQ), alcohols, aromatic solvents or.
• solvents such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSQ), alcohols, aromatic solvents or. Water, at a temperature which will be adapted by man. of wax at the base used and at the solvent used.
• the 2-methoxy-5- [2- (3,4,5-trimethoxy-phenyl) -vinyl] -nitrophenyl is reduced according to the improved process of .invention by faction of iron. It is advantageous to use an excess amount of iron if a complete transformation of the starting material is desired. This excess is advantageously greater than 2 equivalents for one mole of starting nitro derivative.
• a second process has also been found avoiding the intermediate reduction step necessary when part of a nitro derivative.
• it is much more economical to condense according to a first method of implementing this second process, a bromide or a (3,4,5-trimethoxy-benzyl) -triphenylphosphonium chloride with a 3-amino 4-methoxy benzaldehyde or still according to a second method of implementing this second process, 3,4,5-trimethoxybenzaldehyde with a salt of (3-amino-4-methoxy-benzyl) -triphenylphosphonium.
• This second process requires one step less involving CMR products (Carcinogenic, Mutagenic, toxic for Reproduction), compared to the first V0 1 and V0 2 pathways processes, which at the industrial level is an advantage from the point of view safety and considerable production cost.
• route V 03 for implementing the invention the (3,4,5-trimethoxy benzyl) - triphenylphosphonium salt is brought into contact with 3-amino-4-methoxybenzaldehyde, the reaction is started.
• a base chosen from, in particular, potassium terbutylate, sodium teramylate, hydride sodium, butyllithium, LDA, sodium methylate, potassium carbonate or the alkali derivatives of hexamethyldisilanes. It is preferred to use sodium methylate.
• This reaction is carried out in various solvents such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSQ), alcohols, aromatic solvents or water, at a temperature which will be adapted by a person skilled in the art. the base used and the solvent used.
• solvents such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSQ), alcohols, aromatic solvents or water, at a temperature which will be adapted by a person skilled in the art. the base used and the solvent used.
• reaction temperature will be adapted by a person skilled in the art to the base used, when using the methylate, it is preferably between 0 and 10 ° C.
• the base used is neutralized with an acid in aqueous solution, the organic phase is washed, concentrated and the expected product is obtained after chromatography of the crude concentrate.
• the reaction is preferably implemented in the presence of an organic base chosen from in particular potassium terbutylate, sodium teramylate, sodium hydride, butyllithium, LDA, sodium methylate, potassium carbonate or alkaline derivatives hexamethyldisilanes. It is preferred to use sodium methylate.
• This reaction is carried out in various solvents such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSQ.), Alcohols, aromatic solvents or water, at a temperature which will be adapted by the man of Base wax used and solvent used.
• the reaction temperature will be adapted by a person skilled in the art to the base used, when using the methylate, it is preferably between 0 and 10 ° C.
• the base used is neutralized with an acid in aqueous solution, the organic phase is washed, concentrated and the expected product is obtained after chromatography of the crude concentrate.
• the PG group of the formulas (Mb) or (III) represents a protective group chosen from the following groups: ter-butoxycarbonyl, benzyloxycarbonyl (CBZ) or 9-fluorenylmethyloxycarbonyl (FMOC).
• the compound of formula (III) above is new and is claimed as such.
• Coupling to the derivative of formula (Ma) can also be achieved by the action of a mixed anhydride, synthesized in situ between a chloroformate or a chloride carboxylic acid, for example pivaloyl and the doubly protected L-serine of formula (IIb) in the presence of a tertiary base of the NMM type (N-methyl morpholine) in various solvents inert with respect to the reaction, esters, ethers, so chlorinated, acetonitrile, etc.
• Mixed anhydride is preferably prepared at a temperature between 0 and 10 ° C. then the reaction is carried out at room temperature. After reaction, the reaction medium is hydrolyzed with an aqueous solution, then the medium is decanted and the organic phase obtained is washed with a hydroxylated base.
• reaction of an organic or inorganic acid it is preferred to use aqueous concentrated hydrochloric acid in alcoholic medium.
• the reaction temperature is understood according to a better means of implementing the invention between 50 and 70 ° C.
• 3-nitrobenzyl) -triphenylphosphonium and 3,4,5-trimethoxy-benzaldehyde makes it possible to obtain the mixture of Z and E isomers of 2-methoxy-5- [2- (3,4,5-trimethoxy-phenyl) -vinyl] -nitro-phenyl with a ZE ratio of 75/25.
• This ratio is sufficiently high in the nitro Z isomer to be able to directly engage the Z / E mixture in reduction and to obtain, by crystallization, the hydrochloride, the Z amino isomer with an HPLC titer of 97% NI (internal standardization).
• the addition funnel is replaced by a 500 ml isobaric dropping funnel through which 300 ml of distilled water are poured drop by drop in 30 minutes while maintaining the medium at 20 ° C. A gas evolution is observed at the start of casting.
• the medium is concentrated 2/3 on a rotary evaporator (50 ° C / 20 mmHg) a white product crystallizes in the aqueous concentrate in the form of blocks.
• the cooled aqueous phase is extracted with 250 ml then 150 ml of dichloromethane, the combined organic phases are washed with 250 ml of distilled water, then dried over magnesium sulfate.
• 3-nitro-4-methoxy-bromobenzyl (3) The chloromethylenic alcohol solution is charged in a 1 liter three-necked flask fitted with a mechanical stirrer, a thermometer, a Y tube, a dropping funnel and a cooler surmounted by a bubble counter. -nitro-4-benzyl methoxy (2) and 100 ml of dichloromethane are added. The stirred solution is cooled to 5 ° C and then poured drop by drop while maintaining the temperature at 5 ° C, 135.4 g of phosphorus tribromide.
• the medium decanted in an ampoule is washed successively with 250 ml of distilled water and 200 ml of saturated sodium hydrogencarbonate solution.
• the organic phase is dried over magnesium sulfate, filtered and concentrated in a rotary evaporator (50 ° C / 20 mmHg). 119 g of solid are obtained in the form of felted yellow-green needles with a chemical yield over 2 steps of 97%.
• This product (3) can also be prepared according to the following scheme described in the publication K.G. Pineyet al. Bioorg. Med. Chem. 8 (2000) 2417-2425
• the medium is maintained for 4 hours at 60/65 ° C then cooled to 30 ° C, filtered on sintered glass, washed on filter with 2 times 300 ml of toluene, wrung and dried in a drying oven (35 ° C / 20 mmHg / 20 hours).
• the stirred suspension is cooled to 5 ° C. using an ice bath, then 63.2 g of a 25% w / w sodium methoxide solution in methanol are poured at 5 ° C in 40 minutes.
• the suspension changes from off-white to yellow and then to brown.
• the suspension is heated to 40 ° C and maintained for 30 minutes at 40 ° C, at this temperature, only the salts remain insoluble, filtered at 40 ° C on No. 3 sintered glass and the salts are washed on filter by 3 times 100 ml of toluene.
• the filtrate is recharged in a flask with 250 ml of distilled water, the two-phase mixture is stirred for 20 minutes at 40 ° C. and then decanted in an ampoule.
• the toluene phase is washed twice more with 250 ml of distilled water and then concentrated to dryness on a rotary evaporator.
• the pellet is taken up in 600 ml of isopropanol and 12 ml of toluene at 40 ° C., the expected starts to crystallize, the temperature is allowed to return to ambient temperature overnight with slow stirring.
• Solvents THF, acetonitrile, methanol and other alcohols, dichloromethane, NMP, DMF, DMSO, etc.
• Bases potassium t-butoxide, sodium t-amylate, soda, NaH, Buli / LDA, potassium carbonate, etc.
• the mixture is stirred rapidly and the mixture is heated in an oil bath, at 50 ° C., 7.8 ml of 6N hydrochloric acid is added to the suspension, then the temperature of the medium is raised to 77 + 2 ° C, the medium is almost soluble. 52 g of powdered iron are added in 5 minutes in portions. From the first addition the medium goes into solution and then a blackish deposit forms on the walls of the flask.
• the filtrate, mother liquors and washing waters, is concentrated on a rotary evaporator, as soon as the azeotrope has been removed, an oil begins to precipitate in the residual aqueous phase.
• This aqueous phase is extracted in an ampoule with 2 times 300 ml of dichloromethane and then the organic phase is washed with 2 times 300 ml of semi-saturated aqueous solution of sodium chloride and with 300 ml of distilled water.
• the organic phase is concentrated to dryness on a rotary evaporator, 76 g of an oil is obtained which has a Z / E ratio of 80/20 in HPLC.
• This oil is dissolved in 591 ml of methanol and transferred to a stirred 1 liter flask, 100 ml of 2.32N hydrochloric methanol are then added, the mixture is primed and left to precipitate overnight with stirring.
• the quantity of methanol + hydrochloric methanol is such that the final concentration of Z isomer (determined by HPLC) is equal to 8.8% w / v.
• the medium is filtered on sintered glass, the dried cake weighs 8.2 g and is only composed of the E isomer (HPLC).
• the medium is filtered through celite and concentrated in vacuo, 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.
• Phosphonium (2a) is a raw material already described in the original patent Ajinomoto Co., Ltd US 5,525,632 and WO 01/12579 A2.
• this oil contains starting aldehyde of the 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 mixture of cyclohexane / ethyl acetate / triethylamine (50/50/2).
• the first dry extract of 360 mg contains Fisomere Z at 93% + unidentified impurities
• the second of 2.09 g contains starting aldehyde and a Z / E mixture representing 39 and 37 .5% in HPLC NI.
• the interest of the VO 3 route compared to the first VO 2 process known as “reverse Wittig” is to carry out the Wittig reaction between an already reduced product, (3-amino-4- bromide).
• the medium is cooled to 40 ° C. the medium is filtered through clarcel, rinsed with 100 ml of ethanol at 20% water and the filtrate is concentrated to dryness under vacuum on a rotary evaporator.
• the pellet is taken up in 300 ml of isopropanol and crystallizes from the medium, the mixture is stirred and heated to 50 ° C. and the medium goes back into solution. 14 ml of 5N hydrochloric isopropanol are then poured in, the medium precipitates, the mixture is kept at 50 ° C. for 1 hour and then allowed to return to the ambient. The slurry is filtered through a sintered glass, the cake is washed with 50 ml of isopropanol, wrung thoroughly and dried in a vacuum oven.
• the stirred suspension is cooled to 5 ° C. and 4.92 ml of sodium methoxide solution in methanol at 25% w / w are poured in over 15 minutes.
• the suspension is stirred for 2.5 hours at 5 ° C. and then 0.2 ml of acetic acid diluted in 50 ml of water is poured in, the temperature rises to 14 ° C and the medium becomes very thick, diluted with 10 ml of toluene and 10 ml of water, there remains an insoluble brown.
• the mixture is filtered on clarcel, the cake is washed with 3 times 50 ml of toluene (the washes contain practically only starting aldehyde and are not joined to the two-phase filtrate), the clear filtrate (pH 12) is decanted in an ampoule and the organic phase is concentrated to dryness under vacuum at 40 ° C. the Z / E ratio determined by HPLC NI is 43/57.
• the brown oil obtained (4 g) is chromatographed on a silica column (100 parts w / w) eluted with a mixture of cyclohexane / ethyl acetate / triethylamine (50/50/2).
• the weight balance in Z isomer (8 ′) determined by HPLC NI is 0.725 g on 4 g of aldehyde used, ie a yield as it is of 11.3%.
• the organic phase is separated by decantation, dried over sodium sulfate and then filtered.
• 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 hardens at 20 ° C with a weight yield of (8) engaged of 117%.
• the filtrate is recharged in a stirred three-necked flask and 194 ml of isopropyl acetate are added, the mixture is warmed to 40 ° C., the solution is primed with 0.2 g of (12) and then poured dropwise over 1 hour, 194 ml of isopropyl acetate, the medium crystallizes slowly during the pouring.
• the medium is left to return to the ambient temperature then it is cooled and kept overnight at 5 ° C.

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