The way to obtain 7-hydroxy-taxan

 

(57) Abstract:

The way to obtain 7-hydroxy-taxan General formula I, where R1-N, alkoxyl, alkoxyacetic radical, alkanoyloxy radical, Z Is H or a radical of the formula III, R2- bentely radical, possibly substituted by 1 to 2 halogen atoms, alkyl, alkoxyl, CF3or a radical R'2-OCO-, R2'-C1-8alkyl, C2-8alkenyl, R3- C1-8alkyl, phenyl, possibly substituted by alkoxyl, R4, R5- monosubstituted or geminigemini in position 2 oxazolidinones cycle, is in the handling of the compounds of formula II in which R1- C1-4alkyl, possibly substituted by phenyl, triperoxonane acid in an organic solvent of the main character. The method allows for the replacement of trialkylsilyl-by hydroxyl radical without affecting the rest of the molecule. 4 S. p. f-crystals.

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The present invention relates to a method of reception in which the symbols R are identical or different, denote alkyl radicals with 1 to 4 carbon atoms, if appropriate substituted phenyl radical, from 10-desacetyl-baccatin III formula II

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In the General formula (I), each of the symbols R represents preovolos R denotes the ethyl radical.

According to J-N. Denis, and A. E. Greene, J. Am. Chem. Soc. 110, 5917 - 5919 (19. . ), know the product of General formula (I) from 10-desacetyl-baccatin III of the formula (II), which is first selectively similarbut in position 7 tecknologi cycle to obtain 7-trialkylsilyl-10-desacetyl-baccatin III, then selectively will acetimidoyl in position 10 obtained 7-trialkylsilyl-10-desacetyl-baccatin III.

According to the method, the reaction sililirovanie carried out by processing 10-desacetyl-baccatin III excess.

Z denotes a hydrogen atom or a radical of General formula III

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where:

R2means bentely radical, if necessary substituted by one or more atoms or radicals, identical or different, selected among halogen atoms and alkyl radicals with 1 to 4 carbon atoms, CNS radicals with 1 to 4 carbon atoms and trifloromethyl; or denotes a radical R'2-O-CO-, in which R'2does

alkyl radical with 1 to 8 carbon atoms, alkanniny radical with 2 to 8 carbon atoms, an alkyl radical with 3 to 8 carbon atoms, cycloalkyl radical with 3 to 6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms, bicycloalkyl radical with 7 - weberei among halogen atoms and hydroxyl radical, CNS radicals with 1 to 4 carbon atoms, dialkylamino-radicals, each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino-radicals, 1-piperazinilnom radical (if necessary substituted in position 4 alkyl radical with 1 to 4 carbon atoms or phenylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl radicals with 3 to 6 carbon atoms, cycloalkenyl radicals with 4 to 6 carbon atoms, phenyl radical (if necessary substituted by one or more atoms or radicals, selected among halogen atoms and alkyl radicals with 1 to 4 carbon atoms or CNS radicals with 1 to 4 carbon atoms), cyano-, carboxy - or alkoxycarbonyl radicals, the alkyl part of which contains 1 to 4 carbon atoms;

phenyl or - or - nattily radical, if necessary substituted by one or more atoms or radicals selected among halogen atoms and alkyl radicals with 1 to 4 carbon atoms or CNS radicals with 1 to 4 carbon atoms, or an aromatic five-membered heterocyclic radical, preferably selected among fueling or thienyl the Radik necessary substituted by one or more alkyl radicals with 1 to 4 carbon atoms; and

R3denotes a linear or branched alkyl radical with 1 to 8 carbon atoms, linear or branched alkanniny radical with 2 to 8 carbon atoms, linear or branched alkynylaryl radical with 2 to 8 carbon atoms, cycloalkyl radical with 3 to 6 carbon atoms, phenyl, or - or - nattily radical, if necessary substituted by one or more atoms or radicals selected among halogen atoms and alkyl, alkenyl, etkinlik, aryl, kalkilya, CNS, alkylthio, aryloxy, aaltio-, hydroxyl, hydroxyalkyl, mercapto-, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl-, amino-, alkylamino, dialkylamino-, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarboxylic, dialkylammonium, cyano-, nitro - and triptorelin radicals; or

aroma of five-membered heterocycle containing one or more heteroatoms, identical or different, selected among nitrogen atoms, oxygen or sulfur, and, if necessary substituted by one or more, same or different substituents selected among halogen atoms and alkyl, aryl, amino, alkyl, alkylcarboxylic, dialkylammonium or alkoxycarbonyl radicals, and phenyl substituents, or afternova radicals and aromatic compounds, alkyl radicals and alkyl portions of other radicals contain 1 to 4 carbon atoms: and

alkeneamine or alkyline radicals contain 2 to 8 carbon atoms: and

aryl radicals are phenyl or - or - raftiline radicals; and

or R4denotes a hydrogen atom and R5denotes a hydrogen atom or a protective group for the hydroxyl function, or R4and R5together form a saturated 5 - or 6-membered heterocycle.

In the General formula (II), the symbols R are identical or different, represent, each, a linear or branched alkyl radical with 1 to 4 carbon atoms, if appropriate substituted phenyl radical.

Primarily the present invention relates to a method for producing 7-hydroxy-taxan General formula (I) in which R1denotes a hydrogen atom or CNS radical with 1 to 4 carbon atoms, allegeldy radical with 1 to 4 carbon atoms or alkoxyacetic, the alkyl part of which contains 1 to 4 carbon atoms;

Z represents an atom in the O-CO-, in which R'2denotes tert.-botilony radical;

and R3denotes an alkyl radical with 1 to 6 carbon atoms, alkanniny radical with 2 to 6 carbon atoms, cycloalkyl radical with 3 to 6 carbon atoms, phenyl radical, if necessary substituted by one or more atoms or radicals, identical or different, selected among halogen atoms (fluorine, chlorine), alkyl (methyl), CNS (methoxy group), dialkylamino (dimethylamino group), acylamino-(acetylamino group), alkoxycarbonyl-(tert.-butoxycarbonylamino-group) or triptorelin radicals; or 2-purely or 3-purely radical, 2 - or 3-thienyl radical or 2-, 4 - or 5-thiazole radical; or

R4denotes a hydrogen atom and R5denotes a hydrogen atom or methoxymethyl, 1 ethoxy-ethyl, benzoyloxymethyl or tetrahydropyranyl radical; or R4and R5together form monosubstituted or gem-disubstituted in position 2 oxazolidinones cycle.

More specifically, the present invention relates to the production of 7-hydroxy-taxan General formula (I) in which R1denotes the atomic charges radical; Z represents a hydrogen atom or a radical of General forms which denotes tert.-botilony radical; R3means isobutylene, isobutylene, tsiklogeksilnogo, phenyl, 2-purely, 3-furely, 2-thienyl: 3-thienyl, 2-thiazolidines, or 5-diazolidinyl radical; and R4and R5together form oxazolidinone cycle, substituted in position 2, 4-methoxy-phenyl radical.

In European patent application EP-0336840 describes receiving Taxol by simultaneous deletion of the encrypted of ester in the side chain and in taksanova cycle using hydrogen chloride in alcohol, such as ethanol.

According to the invention, the products of General formula (I) are obtained by treatment of the product of General formula (II) triperoxonane acid in an organic solvent, the main character, such as pyridine, if necessary substituted by one or more alkyl radicals with 1 to 4 carbon atoms, if necessary in combination with an inert organic solvent, such as acetonitrile, at a temperature of 20 - 80oC. is Particularly preferable to use a product of General formula (II), in which the symbols R represent, each, ethyl radical.

In particular, working in the conditions of the method according to the invention, the replacement of trialkylsilyl-radical hydroxyl General formula (III), without affecting the protective group denoted by R5or loop formed by R4and R5.

The products of General formula (I) are particularly suitable for obtaining taxidou meets the General formulas IV and V

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in which R1and Z have the above meaning with the formation of an intermediate product of General formula VI

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in which R1and Z have the above meaning.

The products of General formula (IV) can be obtained by exposure of a halide of an alkali metal (sodium chloride, sodium iodide, potassium fluoride or alkali metal azide (sodium azide) or a Quaternary ammonium salt or a phosphate of an alkali metal on a product of General formula (VI) in an organic solvent chosen among ethers (tetrahydrofuran, diisopropyl ether, methyl tert. -butyl ether) and NITRILES (acetonitrile, taken separately or as a mixture, at a temperature of 20oC to the boiling temperature of the reaction mixture.

The products of General formula (V) can be obtained by treating a product of General formula (VI) with a base selected among the organic solvents of the main character, such as pyridine, pyridine substituted by one or more alkyl is s (VI) can be obtained by exposure of a derivative triftoratsetata, such as the anhydride, florangela acid or N-phenyl-triptoreline, working in an inert organic solvent (possibly substituted aliphatic hydrocarbons, aromatic hydrocarbons) in the presence of organic bases, such as tertiary aliphatic amine (triethylamine) or pyridine, at temperatures from -50oC to +20oC.

The products of General formulas (IV) and (V) in which Z denotes a radical of General formula (III) in which R2and R3have the above meaning, R4and R5each represent a hydrogen atom, possess remarkable anti-cancer and antileykemicheskoy properties.

The following examples illustrate the present invention.

Example 1

To a solution of 25 g of 4,10 - diacetoxy-2 - benzoyloxy - 5,20 - epoxy-7 - triethylsilyl-9-oxo-1 - hydroxy-11-taxen-13 - yl-3-tert.-butoxycarbonyl-2-(4-methoxy-phenyl)-4-phenyl-oxazolidin-5-carboxylate-(2R, 4S, 5R) 125 cm3acetonitrile 111 cm3pyridine, cooled to 5oC for 45 minutes add 103,6 g triperoxonane acid. Stirred for 15 hours at 50oC. Add again 28 cm3pyridine and 25.9 g triperoxonane acid and stirred for 10 cha is of 15 hours at 50oC. the Reaction mixture is cooled to 20oC, then poured into 4 l of ice water. The suspension is filtered. The precipitate is washed 10 times with 200 cm3distilled water and dried in air, then washed with 140 cm3diisopropyl ether, sucked off and finally washed 2 times in 46 cm3diisopropyl ether. Thus, with the release of 97%, a gain of 21.7 g of 4,10 - diacetoxy-2 - benzoyloxy-5,20 - epoxy-1,7 - dihydroxy-9-oxo-11-taxen-13-yl-3-tert. -butoxycarbonyl-2-(4-methoxy-phenyl) -4-phenyl-oxazolidin-5-carboxylate-(2R, 4S, 5R) whose characteristics are the following:

So pl. = 178oC.

Range of proton nuclear magnetic resonance (400 MHz; deuterochloroform; temperature 323oK, M. D.: 1,07 (C., 9H: C(CH3)3); 1,12 (C., 3H: - CH3); 1.27mm (C. , 3H: - CH3); 1,58 (C., 3H: - CH3); 1,66 (C., 3H: - CH3): 1,85 and 2,50 (2 MT., 1H each: - CH2at position 6); 1,86 (C., 3H: COCH3); 2,13 and of 2.21 (2 DD. , J = 16 and 9 Hz, 1H each: - CH2at position 14); 2,24 (C., 3H: COCH3); 3,72 (D., J = 7 Hz, 1H: H at position 3); 3,82 (C., 3H: OCH3); 4,12 and 4,24 (2 days, J = 8 Hz, 1H each: - CH2in position 20); to 4.38 (DD., J = 11 and 6 Hz, 1H: H at position 7); 4,58 (D., J = 5.5 Hz, 1H: H at position 2); 4,89 (DD., J = 10 and 3.5 Hz, 1H: H at position 5); 5,43 (D., J = 5.5 Hz, 1H: H at position 3); 5,63 (D. , J = 7 Hz, 1H: H at position is B>H5H in the position ortho to the OCH3); 7,30 - to 7.50 (MT. , 7H: C6H53' and C6H5in metaprogram to OCH3); of 7.48 (t, J = 8.5 Hz, 2H: -OCOC6H5H at the meta position); to 7.2 (t, J = 8.5 Hz, 1H: -OCOC6H5H in the para-position); 9,03 (D., J = 8.5 Hz, 2H: -OCOC6H5H in the ortho-position).

4,10 - Diacetoxy-2 - benzoyloxy-5,20 - epoxy-7 - triethylsilyl-9-oxo-1 - hydroxy-11-taxen-13 - yl-3-tert.-butoxycarbonyl-2-(4-methoxy-phenyl)-4-phenyl-oxazolidin-5-carboxylate (2R, 4S, 5R) can be obtained as follows.

To a solution of 147 g of 7-triethylsilyl-baccatin 111 and 100 g of 3-tert.butoxycarbonyl-2-(4-methoxy-phenyl)-4-phenyl-oxazolidin-5-carboxylic acid 720 cm3ethyl acetate, cooled to a temperature of about 5oC, successively added to 64.7 g of 1,3-DICYCLOHEXYL-carbodiimide and 5.6 g of 4-dimethylamino-pyridine.

The thus obtained suspension is stirred for 4 hours at 20oC, then filtered. The filters are washed with 2 times 500 cm3water Polynesians solution of sodium bicarbonate, 2 times 500 cm3distilled water and 2 times 500 cm3aqueous saturated solution of sodium chloride.

The organic phase is dried over magnesium sulfate. After Hotfile is SUP> methyl-tert.-butyl ether and receive 126,9 g of 4-,10 - diacetoxy-2 - benzyloxy-5,20 - epoxy-7 - triethylsilyl-9-oxo-1 - hydroxy-11-taxen-13 - yl-3-tert.-butoxycarbonyl-2-(4-methoxy - phenyl)-4-phenyl-oxazolidin-5-carboxylate-(2R, 4S, 5R)-the characteristics of which are the following:

So pl. = 174oC;

Range of proton nuclear magnetic resonance (400 MHz, deuterochloroform, M. D.): 0,58 (MT., 6H; CH2); to 0.92 (t, J=7.5 Hz, 9H; CH3); 1,02 (C. , 3H, CH3); 1,18 (C., 3H; CH3); 1,68 (C., 3H; CH3); 1,75 (n, 1H: OH at position 1); 1,87 and 2,53 (2MT, 1H each: - CH2at position 6); 2,18 (c. 6H: CH3and COCH3); 2,27 (MT., 2H: CH at position 14); 2,28 (C., 3H: COCH3); 2,47 (n 1H: OH at position 13); 3,88 (d, J=7 Hz, 1H: H at position 3); 4,13 b 4,30 (2D., J=8.5 Hz, 1H each: - CH2in position 20); 4,50 (DD., J=11 and 7 Hz, 1H: H at position 7) to 4.81 (MT., 1H: H at position 13); 4,95 (D. W., J=10 Hz, 1H: H at position 5); 5,63 (D., J=7 Hz, 1H: H at position 2); 6,46 (C., 1H: H at position 10); 7,46 (t, J=8.5 Hz, 2H: -OCOC6H5H at the meta position); 7,60 (t , J=8.5 Hz, 1H: -OCOC6H5H in the para-position); 8,10 (D., J=8.5 Hz, 2H: -OCOC6H5H in the ortho-position).

7-Triethylsilyl-baccatin 111 can be obtained as follows.

To a solution of 293,9 g 10-desacetyl-baccatin 111 2.7 l of pyridine for 1 hour and 20 minutes add 182 g t the red anhydride, maintaining the temperature of the 5oC. the resulting suspension is stirred for 48 hours at 20oC, then poured into 40 l of water with ice. The obtained precipitate was separated by filtration, then washed 8 times with 2 l of water, and finally dissolved in 3 l of ethyl acetate. The organic phase is dried over magnesium sulfate. After filtration and concentration under reduced pressure, the resulting product is crystallized from diisopropyl ether. Thus, with the release of 77%, get 7-triethylsilyl-baccatin 111, the characteristics of which are the following:

So pl. = 254oC.

Range of proton nuclear magnetic resonance (400 MHz, deuterochloroform, M. D.): 0,58 (MT., 6H: CH2, ethyl); to 0.92 (t, J=7.5 Hz, 9H: CH3, ethyl); 1,02 (C., 3H: - CH3); 1,18 (C., 3H: - CH3); 1,68 (C., 3H: - CH3); 1,75 (n, 1H: OH at position 1); 1,87 2,53 and (2 MT, 1H each: - CH2at position 6); 2,18 (C. , 6H: CH3and COCH3); 2,27 (MT., 2H: CH2at position 14); 2,28 (C., 3H: COCH3); 2,47 (n, 1H; OH at position 13); 3,88 (D., J=7 Hz, 1H: H at position 3); 4,13 and 4,30 (2D., J=8.5 Hz, 1H each: - CH2in position 20); 4,50 (DD. , J=11 and 7 Hz, 1H: H at position 7); 4,18 (MT., 1H: H at position 13); 4,95 (D. W., J=10 Hz, 1H: H at position 5); 5,63 (D., J=7 Hz, 1H: H at position 2); 6,46 (C., 1H: H at position 10); 7,46 (t, J=8.5 Hz, 2H: -OCOC6H5Nrto-position).

Example 2.

To a solution of 350 mg of 7-triethylsilyl-baccatin 111 3 cm3acetonitrile and 2,4 cm3pyridine add 2.3 g triperoxonane acid. Stirred for 48 hours at 50oC. after cooling, the reaction mixture was absorbed with 50 cm3of methylene chloride, washed with 2 times 5 cm3distilled water, 10 cm31N hydrochloric acid and 2 times of 5 cm3distilled water and dried over magnesium sulfate. After filtration and concentration to dryness under reduced pressure to obtain 330 mg of product, which is purified by chromatography on 30 g of silica contained in a column 2 cm in diameter, elwira mixture of methylene chloride with methanol (99:1 by volume). The first 300 cm3that elute, cast. 275 cm3the following eluates, after concentration to dryness, to give 235 cm baccatin in the form of a foamy product is white. Yield = 83%.

1. The way to obtain 7-hydroxy-taxan General formula I

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in which R1denotes a hydrogen atom or CNS radical with 1 to 4 carbon atoms, alkoxyacetic-radical, the alkyl part of which contains 1 to 4 carbon atoms, or alkanoyloxy with 1 to 4 carbon atoms,12denotes an alkyl radical with 1 to 8 carbon atoms, alkanniny radical with 2 to 8 carbon atoms;

R3denotes a linear or branched alkyl radical with 1 to 8 carbon atoms, phenyl, and, if necessary substituted by one or more C1- C4CNS radicals;

R4and R5together form a mono-substituted or geminigemini in position 2 oxazolidinones cycle

characterized in that the product of General formula II

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in which R1and Z have the above meanings and the symbols R1identical or different, represent, each, a linear or branched alkyl radical with 1 to 4 carbon atoms, if appropriate substituted phenyl radical, process triperoxonane acid in an organic solvent of the basic character.

2. The method according to p. 1, wherein the organic basic solvent vroda.

3. The method according to p. 1 or 2, characterized in that operate at 20 - 80oC.

4. The method according to any of paragraphs.1 to 3, characterized in that a product of General formula I, in which R1denotes a hydrogen atom or CNS radical with 1 to 4 carbon atoms, acyloxy radical with 1 to 4 carbon atoms or alkoxyacetic-radical, the alkyl part of which contains 1 to 4 carbon atoms; Z represents a hydrogen atom or a radical of General formula III in which R2means bentely radical or a radical in which R12denotes tert. -botilony radical, R3denotes an alkyl radical with 1 to 6 carbon atoms, phenyl radical, if necessary substituted by one or more and CNS radicals (methoxy group), and R4and R5together form monosubstituted or gem-disubstituted in position 2 oxazolidinones cycle.

5. The method according to any of paragraphs.1 to 3, characterized in that a product of General formula I, in which R1denotes the atomic charges radical; Z represents a hydrogen atom or a radical of General formula III in which R2means bentely radical or a radical in which R12denotes tert.-botilony radical; R3oboznachaet 4-methoxy-phenyl radical.

 

Same patents:

The invention relates to a new method of obtaining 7-trialkylsilyl-baccatin III General formula 1

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in which the symbols R are identical or different, denote alkyl radicals with 1-4 carbon atoms, if appropriate substituted phenyl radical, from 10-desacetyl-baccatin III formula II

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In the General formula (1) each of the symbols R represents preferably a linear or branched alkyl radical with 1-4 carbon atoms
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The invention relates to methods for taxan with side chain and their intermediates and to new compounds of the formula III obtained by these methods

The invention relates to new derivatives taxane III formula 1 in which R1- H; R14- H, C2-C9-alkanoyl, unsubstituted by halogen atom, or R1and R14taken together, represent a carbonyl or lower alkylidene; R7= R10- H, three(lower alkyl)silyl or C2-C9-alkanoyl, unsubstituted or mono-, di-, tizamidine a halogen atom; R13- H, -COCHOHCH-(C6H5) NHCOC6H5or COCHOHCH (C6H5)NHCOOC(CH3)3-group; AC is acetyl, these compounds possess anti-tumor activity

The invention relates to a method for producing derivatives taxane General formula (I) by esterification of protected baccatin III or protected 10-desacetyl-baccatin III using the acid of General formula (II)

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivative of taxane of the formula (I):

that elicits strong antitumor effect. Also, invention relates to intermediates substances, a method for preparing compound of the formula (I), a method for preparing 1,14-β-hydroxy-1,14-carbonate-baccatin III-derivatives substituted with isoserine residue at position 3 and to pharmaceutical composition based on compounds of the formula (I). Invention provides preparing new derivative of taxane that elicits higher activity and reduced toxicity as compared with paclitaxel.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compound.

10 cl, 7 tbl, 6 ex

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EFFECT: valuable medicinal properties of compound.

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6 cl, 1 tbl, 7 ex

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EFFECT: valuable medicinal property of compounds.

5 cl, 5 ex

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EFFECT: improved preparing method.

8 cl, 8 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to derivatives of taxane of the general formula (I):

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98 cl, 6 ex

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EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

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7 cl, 2 tbl, 6 ex

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EFFECT: improved preparing method.

11 cl, 2 tbl, 8 ex

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EFFECT: improved preparing method.

9 cl, 11 ex

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