Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

• the present invention relates to a process for the preparation of new derivatives of ⁇ -phenylisoserine of general formula:
• R represents a t-butoxy or phenyl radical and Ar represents an aryl radical chosen from phenyl or ⁇ - or ⁇ -naphthyl radicals optionally substituted by one or more atoms or radicals, identical or different, chosen from atoms '' halogen and the alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, hydroxy, mercapto, amino, monoalkoylamino, dialcoylamino, acylamino, alkoxycarbonylamino, carboxy, carbamoyl, N, N-dialkoyluoremethyl, or cyanoometro-racemic, cyanoometric, or nitrofluorochemical radicals pure or in the form of their mixtures, optionally in the form of a salt or an ester.
• Ar represents an aryl radical chosen from phenyl or ⁇ - or ⁇ -naphthyl radicals optionally substituted by one
• R'i represents an acetyl radical or a protective group for the hydroxy function and G2 represents a protective group for the hydroxy function, followed by the replacement of the protective groups, which are preferably chosen from 2,2,2-trichloro radicals ethoxycarbonyl and trialkylsilyl, each alkyl part of which contains 1 to 4 carbon atoms, through hydrogen atoms.
• the use as a protective group of the 1-ethoxy ethyl radical introduces, on the one hand, a methyl radical which can have a steric influence on re-esterification and, on the other hand, an unsolved asymmetric carbon atom which results in the presence of two stereoisomers making the purification processes difficult.
• the 2,2,2-trichloroethoxymethyl protective group of the product of general formula (I) has the following advantages: it is very stable under the usual conditions of basicity and acidity, - it does not have an asymmetric carbon atom causing stereoisomerism problems or grouping inducing steric effects,
• the present invention therefore relates to the preparation of the new product of general formula (I) optionally in the form of a salt or ester and its use for preparing the taxane derivatives of general formula (II).
• the product of general formula (I) can be obtained by the action of a halide, preferably bromide, of 2,2,2-trichloroethoxymethyl on a product of general formula which can be in racemic form or ena ⁇ tiomerically pure or in the form of their mixtures:
• the action of 2,2,2-trichloroethoxymethyl halide on the product of general formula (V) is carried out by operating in an anhydrous organic solvent such as acetonitrile at a temperature between 0 and 50 °. C, and preferably around 20 ° C. It is particularly advantageous to operate in the presence of a proton acceptor such as 1,8-bis- (dimethylamino) naphthalene (or "proton sponge"), 2-methyl-butene-2 and a desiccant such as 3 ⁇ or ⁇ molecular sieve.
• Z represents an ester-COOR2 function, R2 being an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical, the product obtained is saponified to the acid of general formula (I).
• the saponification is carried out using a mineral base under conditions which do not affect the rest of the molecule.
• the saponification can be carried out by means of an alkaline carbonate such as potassium carbonate in a hydroalcoholic medium such as a water-methanol mixture.
• the product obtained is oxidized to the acid of general formula (I).
• the oxidation is carried out using a periodate such as sodium periodate in the presence of a catalytic amount of a ruthenium salt such as ruthenium chloride RUCI3.
• the reaction is carried out in a homogeneous or heterogeneous hydroorganic medium.
• solvent can be used acé ⁇ tonitrile and carbon tetrachloride.
• the reaction can be carried out in a basic medium, for example in the presence of sodium hydrogencarbonate.
• the oxidation can also be carried out by means of potassium permanganate, for example in the presence of adogen in a pentane-water mixture or in the presence of aliquat or of dicyclohexyl-18 crown-6 in dichloromethane or in a mixture pyridine-water.
• the double anionization of the product of general formula (VI) is generally carried out using 2 equivalents of an organolithium derivative such as s-butyllithium, operating in an anhydrous organic solvent such as tetrahydrofuran at a lower temperature. at -50 ° C.
• the reaction of acrolein with the dianion of the product of formula (VI) is generally carried out by adding acrolein, preferably freshly distilled to the solution of the dianion previously cooled to a temperature between -50 to -100 ° C, preferably around -100 ° C.
• acrolein preferably freshly distilled
• the product of formula (V) is obtained in the form of a mixture of syn and anti diastereoisomers from which the syn form is optionally separated by chromatography
• the alcohol of general formula (V) is obtained by adding the aldehyde to a solution of a vinyl magnesium halide, preferably vinyl magnesium bromide, in an inert organic solvent such as tetrahydrofuran, possibly in a mixture. with methylene chloride.
• a vinyl magnesium halide preferably vinyl magnesium bromide
• an inert organic solvent such as tetrahydrofuran
• the oxidation of the alcohol of formula (VII) is carried out by means of the oxalyl chloride-dimethyl sulfoxide mixture at a temperature below 0 ° C in an organic solvent such as methylene chloride or tetrahydrofuran in the presence of 'an organic base such as triethylamine or diisopropylethylamine.
• a reducing agent Either by the action of a reducing agent on the acid obtained by the action of an agent which allows both to introduce a t-butoxycarbonyl or benzoyl group on the amino acid of general formula (VIII).
• reducing agent lithium aluminum hydride or borane (BH3) is preferably used, preferably in the form of a complex with dimethylsulfide in the presence of boron trifluoride etherate.
• the reaction is carried out in an organic solvent such as for example an ether such as tetrahydrofuran or dimethoxvethane.
• the reduction is carried out at a temperature between 50 and 100 ° C.
• agent for introducing a t-butoxycarbonyl or benzoyl group use is preferably made, depending on the case, of di-t-butyl dicarbonate or benzoyl chloride.
• an organic solvent such as methylene chloride or an ether such as tetrahydrofuran or dimethoxyethane in the presence of a mineral base such as sodium hydroxide or bicarbonate or sodium car ⁇ bonate or a base organic such as triethylamine or 4-dimethylamino pyridine.
• a mineral base such as sodium hydroxide or bicarbonate or sodium car ⁇ bonate
• a base organic such as triethylamine or 4-dimethylamino pyridine.
• the reaction is carried out between 0 ⁇ C and the reflux temperature of the reaction mixture.
• the acid of general formula (I), optionally in the form of a salt or an ester, obtained according to the process of the present invention can be purified by physical methods such as crystallization or chromatography.
• the product of general formula (I) (syn or syn-anti form, racemic mixture) can also be split into its syn enantiomers, for example by formation of a salt with an optically active base such as ephedrine or pseudo- ephedrine then hydrolysis of the salt obtained.
• the acid of general formula (I) is useful, in particular, for preparing the taxane derivatives of general formula (II).
• the products of general formula (II) are obtained by esterification of the alcohol of general formula (IV), followed by the replacement of the protecting groups for the hydroxy functions by hydrogen atoms and optionally by the separation of the 2R.3S enantiomers .
• esterification is carried out in an aromatic hydrocarbon
• benzene, toluene, xylene at a temperature between 20 and 80 ° C in the presence of a condensing agent such as dicyclohexylcarbodiimide or 2-dipyridylcarbonate and an activating agent such as 4-dimethylamino pyridine.
• a condensing agent such as dicyclohexylcarbodiimide or 2-dipyridylcarbonate
• an activating agent such as 4-dimethylamino pyridine.
• the replacement by hydrogen atoms of the protective groups R ′ j , G j and G2, when they represent a 2,2-trichloro-2,2,2 ethoxycarbonyl or 2,2-trichloro-2,2,2 ethoxymethyl radical is generally carried out by means of zinc or a zinc-copper couple in the presence of acetic acid and optionally an alcohol containing 1 to 3 carbon atoms at a temperature in the region of 60 ⁇ C.
• G2 is a trialkylsilyl radical each part of which contains 1 to 4 carbon atoms
• the replacement of this radical by a hydrogen atom is carried out by an acidic subsequent treatment (for example hydroalcoholic HC1).
• an acidic subsequent treatment for example hydroalcoholic HC1.
• - infrared spectrum film: main absorption bands characteristic at 3450, 3000, 2925, 1760. 1720, 1500, 1460, 1440, 1370, 1175, 1130, 1090, 1020, 950 and
• the aqueous phase is cooled to 0 ⁇ C and then is acidified with 4 cm3 of 2M hydrochloric acid, with vigorous stirring, in the presence of 30 cm3 of methylene chloride. After decantation, it is then extracted 8 times with 20-25 cm3 of methylene chloride.
• the combined organic phases are washed 4 times with 10 cm3 of water and then with 10 cm3 of a saturated aqueous solution of sodium chloride. After drying over anhydrous magnesium sulphate, filtration and concentration to dryness under reduced pressure, a yield of 89.170 mg (0.384 mmol) of t-butoxycarbonylamino-3-phenyl-3 (2,2-trichloro-2,2) acid is obtained.
• - infrared spectrum film: main absorption bands characteristic at 3500-2300, 3000, 2940, 1760, 1730, 1500, 1460, 1400, 1375, 1260, 1180, 1135, 1090.
• - infrared spectrum film: characteristic absorption bands at 3460, 3380, 3080, 3050, 3020, 3000, 2950, 2910, 1720. 1500. 1400, 1370, 1290, 1255, 1170, 1130.
• M ++ 2 (426.5); M ++ 4 (428.5); M ++ 6 (430.5): 4 peaks with ratio 100; 97.5; 31.7 and 3.4
• the reaction medium is left to react with vigorous stirring for 29 hours at a temperature in the region of 20 ° C., then the reaction mixture is diluted with water until a total volume of 20 cm 3 is obtained.
• the basic aqueous phase is washed 3 times with 10 cm3 ether and then cooled to 0 ° C.
• 2 cm3 of 2M hydrochloric acid are added, with vigorous stirring.
• the aqueous phase is extracted 8 times with 40 cm3 of methylene chloride.
• the organic phases are combined and washed 3 times with 10 cm 3 of water then with 10 cm 3 of a saturated aqueous solution of sodium chloride and finally dried over a sodium sulfate-anhydrous magnesium sulfate mixture.
• the crystals thus obtained are dissolved hot in 2 cm3 of methanol. 0.5 cm3 of ethyl acetate are added and then the mixture is cooled to a temperature in the region of 20 ° C. The white crystals formed are separated by filtration and then treated with aqueous IN hydrochloric acid in dichloromethane at a temperature in the region of 20 ° C.
• the mother liquors obtained during the first crystallization are concentrated to dryness.
• the residue is dissolved hot in 2.5 cm3 of methanol. 0.5 cm3 of ethyl acetate are added. After cooling to 20 ° C., 78 mg of white crystals are obtained, after separation by filtration, which are mixed with the residue obtained by dry concentration of the crystallization mother liquors of (+) - tbutoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) -2 propionic- (2R.3S).
• the resolution yield is 83.
• the reaction mixture is treated with a saturated solution of sodium hydrogen carbonate for 10 minutes. 80 cm3 of dichloromethane and 4 cm3 of water are then added to the resulting mixture. After decantation, the aqueous phase is extracted twice with 15 cm3 of dichloromethane. The combined organic phases are washed twice with 8 cm 3 of a 2M aqueous hydrochloric acid solution, 4 times with 8 cm 3 of water and 2 times with 8 cm 3 of a saturated solution of sodium chloride.
• 3 cm3 is then added (2.5 g, 44.9 mmol) of freshly distilled acrolein was allowed to react for 3 to 4 minutes at this temperature then for 3 hours at -78 ⁇ C.
• the resulting reaction mixture is hydrolyzed to -78 ⁇ C with 20 cm3 of water, then it is extracted with 2 times 30 cm3 of ether.
• the organic phases are combined and then they are washed twice with 20 cm3 of water and once with 10 cm3 of a saturated aqueous solution of sodium chloride. They are then dried over anhydrous sodium sulfate. After filtration, the solvents are removed under reduced pressure.
• the acidic aqueous phase is separated by decantation and is then extracted 8 times with 17 cm3 of dichloromethane.
• the organic phases are combined and then washed 4 times with 4 cm3 of water and 2 times with 4 cm3 of an aqueous solution saturated with sodium chloride. After drying over anhydrous sodium sulphate, filtration and concentration to dryness under reduced pressure, 75 mg (0.17 mmol) of ( ⁇ ) -tbutoxycarbonylamino-3-phenyl-3 (2,2,2-trichloroethoxymethoxy) acid are obtained.
• the yield is 71%.
• EXAMPLE 7 701 mg (1.584 mmol) of the product obtained in Example 6 is dissolved in 4 cm3 of acetone in a 25 cm3 flask. It is slightly heated until a homogeneous solution is obtained. A solution of 277 mg (1.69 mmol) of (+) - ephedrine in 4 cm3 of acetone is then added. Stir until a homogeneous solution is obtained. After cooling to a temperature in the region of 20 ° C., the crystals obtained are separated by filtration and washed twice with ether. After drying, 385 mg of ephedrine salt is obtained.
• the crystals thus obtained are dissolved in hot in a mixture of 6 cm3 of methanol and 2 cm3 of ethyl acetate. After evaporation of 10% of the solvent and cooling to a temperature of 20 C C, the crystals obtained are separated by filtration. 190 mg of ephedrine salt are thus obtained in the form of white crystals which are treated with IN hydrochloric acid in the presence of dichloromethane at a temperature in the region of 20 ° C. After extraction according to the usual methods, 138 mg (0.313 mmol) of (+) - t.butoxycarbonylamino-3-phenyl-3 (2,2,2-ethoxymethoxy) -2 propionic acid - (2R.3S) are obtained. ) for which the enantiomeric excess is greater than 99%.
• the yield is 19.8%.
• the mother liquors for recrystallizing the ephedrine salt from the methanol-ethyl acetate mixture are concentrated to dryness.
• the residue obtained is dissolved hot in a mixture of 3 cm3 of methanol and 1 cm3 of ethyl acetate. After evaporation of 10% of the solvent and cooling to a temperature in the region of 20 ° C. for 24 hours, 92 mg of white crystals are obtained, after filtration, which are treated with IN hydrochloric acid in the presence of dichloromethane.
• the organic phase is washed with 5 cm 3 of water, 2 times 5 cm 3 of a saturated aqueous solution of sodium bicarbonate, 4 times 5 cm 3 of water and 2 times 5 cm 3 of a saturated aqueous solution of sodium chloride, then finally dried over anhydrous sodium sulfate. After filtration and concentration to dryness under reduced pressure, the residue obtained (270 mg) is purified by chromatography on a thin layer of silica, eluting with a methylene chloride-ether mixture (95-5 by volume; 2 passages).
• reaction mixture is then treated with 5 cm 3 of a saturated aqueous solution of sodium bicarbonate for 10 minutes. Then added 100 cm3 of methylene chloride and 10 cm3 of water. After decantation, the aqueous phase is extracted twice with 15 cm3 of methylene chloride. The combined organic phases are washed with 2 times 5 cm 3 of an aqueous solution of 2N hydrochloric acid, 4 times with 10 cm 3 of water and 2 times with 10 cm 3 of a saturated aqueous solution of sodium chloride.
• reaction medium is left to react for 23 hours at a temperature in the region of 20 ° C., followed by addition of 643 mg (3 mmol) of "proton sponge” and 485 mg (2 mmol) of 2,2,2-trichloroethoxymethyl bromide and then shake for 24 hours. A further 242 mg (1 mmol) of 2,2,2-trichloroethoxymethyl bromide is added and the mixture is left to react for 20 hours.
• 10 cm 3 of a saturated aqueous sodium hydrogencarbonate solution are added and the mixture is stirred for 15 minutes. 100 cm3 of dichloromethane are added.
• the separated aqueous phase is extracted twice with 10 cm 3 of dichloromethane.
• the highly heterogeneous reaction mixture is then stirred for 5 minutes (gassing) and then 24.8 mg of RUCI3 is added all at once. Is left to react the reaction mixture went dark for 40 hours at a temperature of 15 ⁇ C. the reaction is complete, is added 15 cm3 of water.
• the basic aqueous phase is washed 3 times with 20 cm 3 of ether.
• the aqueous phase is cooled to 0 ° C. and then, with vigorous stirring, is treated, in the presence of 50 cm3 of dichloromethane, with 2.5 cm3 of a 2M aqueous hydrochloric acid solution.
• the acidic aqueous phase thus obtained is extracted 7 times with 70 cm3 of dichloromethane.
• EXAMPLE 15 In a 5 cm3 single-color flask. equipped with a magnetic stirring system, 52 mg of ( ⁇ ) -phenyl-l benzoylamino-1 (2,2,2-trichloroethoxymethoxy) -2 butene-3 syn are introduced under an argon atmosphere obtained in Example 12 (0.12 mmol) dissolved in 0.25 cm3 of acetonitrile. 0.25 cm3 of carbon tetrachloride, 0.37 cm3 of distilled water are then added successively and, with stirring, 65.5 mg solid sodium hydrogencarbonate (0.78 mmol). Then 141 mg of sodium periodate (0.66 mmol) are added in small portions.
• the mixture is stirred for 5 minutes and then 5.2 mg of RUCI3 are added all at once.
• the reaction mixture which has turned black, is left to react for 72 hours at a temperature of 16-17 ° C. Again 3 mg of catalyst are added and then the mixture is stirred for 44 hours at 25-30 ° C. 3 cm3 of water are then added.
• the basic aqueous phase is washed 3 times with 4 cm 3 of ether.
• the aqueous phase is cooled to 0 ° C. and then, with vigorous stirring, is treated, in the presence of 10 cm 3 of dichloromethane, with 0.5 cm 3 of an aqueous solution of 2M hydrochloric acid.
• the acidic aqueous phase thus obtained is extracted 8 times with 10 cm 3 of dichloromethane.
• the resolution yield is 52%.
• EXAMPLE 17 62 mg of (+) - 3-benzoylamino-3-phenyl (trichloro) acid is introduced into a 5 cm 3 monocolour flask fitted with a magnetic stirring system, under an argon atmosphere. -2.2.2 ethoxymethoxy) -2 propionic (2R.3S) (0.139 mmol) dissolved in 1.16 cm3 of anhydrous toluene. 30 mg of dipyridyl-2 carbonate (0.139 mmol) are then added and the mixture is left to react for 5 minutes at a temperature in the region of 20 ° C.
• the organic phase is washed with 3 cm3 of water, twice with 3 cm3 of a saturated aqueous hydrogen carbonate solution sodium, 4 times with 3 cm3 of water and 2 times with 3 cm3 of a saturated solution of sodium chloride and then it is dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent under reduced pressure, the residue obtained (75 mg) is purified by preparative chromatography on a thin layer of silica, eluting with an ether-dichloromethane mixture (8-92 by volume) (3 passages).
• reaction mixture is cooled to a temperature in the region of 20 ° C. and then filtered. The solid is washed with 3 times 0.6 cm 3 of 95% ethanol. To the resulting clear solution, 70 mg of 33% (w / v) hydrochloric acid is added, then the reaction is left to react for 8 hours at a temperature in the region of 20 ° C.
• reaction mixture is diluted with 60 cm 3 of ethyl acetate. The organic phase is washed 2 times with 5 cm3 of a saturated aqueous solution of sodium hydrogencarbonate then 4 times with 5 cm3 of water and 1 time with 5 cm3 of a saturated aqueous solution of sodium chloride.

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