The method of producing paclitaxel and intermediate products for its partial synthesis

 

The invention relates to a new method of obtaining paclitaxel - anticancer agent and intermediate products for its partial synthesis: the compound of formula (II)where a represents a group ofR1the protection group of the hydroxyl or hydrogen atom, and R2is a hydrogen atom, and the compound of formula (III)where each of the groups R4and R5- aryl, and each of the groups R6and R7- halogenated methyl. The technical result - the way to get paclitaxel and its analogues with the application of new intermediate products. 3 S. and 7 C.p. f-crystals, 1 table.

Description text in facsimile form (see graphic part).

Claims

1. Intermediate product for use in the partial synthesis of paclitaxel General formula (II)
where a represents a group

R1the protection group of the hydroxyl or hydrogen atom;
R2- the hydrogen atom.

2. The intermediate product under item 1, in which R1- group a or acetyl.

3. The intermediate product under item 1, in which R1

5. Intermediate product for use in the partial synthesis of paclitaxel General formula (III)

where each of the groups R4and R5- aryl;
each of the groups R6and R7- halogenated methyl.

6. The intermediate product under item 5, in which R4and R5are family, and each of the groups R6and R7is a group ClCH2-, Vgsn2or F3With-.

7. The method of producing paclitaxel, including (i) obtaining an intermediate compound by the reaction of 10-deacetylbaccatin III with tert-butoxypropan obtaining 7-tert-butoxycarbonyl-10-deacetylbaccatin III, (ii) acetylation of 7-tert-butoxycarbonyl-10-deacetylbaccatin III in position 10 with getting 7-tert-butoxycarbonylamino III, (iii) introduction group

in which R3the protection group of hydroxyl, for example, tert-butoxycarbonyl, methoxymethyl, 1-ethoxyethyl, benzoyloxymethyl,-dialkyldithiocarbamate in which each alkyl group contains from 1 atom to 3 carbon atoms, tetrahydropyranyl or 2,2,2-trichlorocyanuric, or a hydrogen atom,
in position 13 7-tert-butoxy the

where each of the groups R4and R5is phenyl;
each of the groups R6and R7-halogenated methyl;
(iv) selective cleavage of groups a and R3in acidic medium under mild conditions using a mineral or organic acid.

8. The method according to p. 7, in which each group R6and R7is a group Cl2-, Vgsn2or F3C-.

9. The method according to p. 7 or 8, in which is used an excess of 7-tert-butoxycarbonylamino III in relation to a derivative of oxazolidine.

10. The method according to p. 7, in which acetylation is produced with the use of acetyl halide or diketene.

 

Same patents:

The invention relates to chemistry, in particular to pharmaceutical chemistry, and can be used for the production of anticancer drug

Derivatives taxane // 2188198

The invention relates to a derivative of 7- (alkoxycarbonyl-substituted) -10-hydroxy-taxan following formula 3b:

< / BR>
in which R1, R2, R4, R5, R6and R14defined above

The invention relates to new derivatives of 10-deazetil-14-hydroxyacetone III of formula 1, where X represents a group >C=S, >C=NH or >S=O; OR1which can beororiented, represents hydroxy, alkylsilane (preferably triethylsilane, O-TES); R2isororiented hydroxy group or Troc group (Troc= Cl3CCH2COO-), or with the carbon atom to which it is attached, forms ketogroup; R3is izoterikoy residue of formula 2; R4is a linear or branched alkyl or alkenylphenol group having 1 to 5 carbon atoms; R5is alkyl having 1 to 5 carbon atoms or tert-butoxypropyl

The invention relates to new intermediate products for poluentes taxan and methods for their preparation

The invention relates to new taxoids General formula (I)

< / BR>
in which Rameans a hydrogen atom or a hydroxyl radical, CNS radical with 1-4 carbon atoms, acyloxy radical with 1-4 carbon atoms or alkoxyacetic-radical, the alkyl part of which contains 1-4 carbon atoms;

Rbmeans a hydrogen atom; or

Raand Rbtogether with the carbon atom to which they are bound, form a ketone function;

Z means a hydrogen atom or a radical of General formula (II)

< / BR>
in which R1means bentely radical, possibly substituted by one or more identical or different atoms or radicals selected among halogen atoms and alkyl radicals with 1-4 carbon atoms, CNS radicals with 1-4 carbon atoms or trifloromethyl; tenor or furoyl, or the radical R2-O-CO-, in which R2means:

is an alkyl radical with 1-8 carbon atoms, alkanniny radical with 2-8 carbon atoms, alkynylaryl radical with 3-8 carbon atoms, cycloalkenyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 atoms in or more substituents, selected among halogen atoms and hydroxyl radical, CNS radical with 1-4 carbon atoms, dialkylamino radical, each alkyl portion of which contains 1-4 carbon atoms, piperidino radical, morpholino radical, piperazine-1-ilen radical (possibly substituted in position 4 alkyl radical with 1-4 carbon atoms or phenylalkyl radical, the alkyl part of which contains 1-4 carbon atoms), cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms, phenyl radical (possibly substituted by one or more atoms or radicals, selected among halogen atoms and alkyl radicals with 1-4 carbon atoms or CNS radicals with 1-4 carbon atoms), a cyano radical, carboxyl or alkoxycarbonyl, the alkyl portion of which contains 1-4 carbon atoms;

is phenyl or- or-nattily radical, possibly substituted by one or more atoms or radicals selected among halogen atoms and alkyl radicals with 1-4 carbon atoms or CNS radicals with 1-4 carbon atoms; or a heterocyclic aromatic patterollers radical with 4 to 6 carbon atoms, possibly substituted by one or more alkyl radicals with 1-4 carbon atoms;

R3means a linear or branched alkyl radical with 1-8 carbon atoms, a linear or branched alkanniny radical with 2-8 carbon atoms, linear or branched alkynylaryl radical with 2-8 carbon atoms, cycloalkyl radical of 3-6 carbon atoms, phenyl or- or-nattily radical, possibly 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, karamolegos, alkylcarboxylic, dialkylanilines, cyano-, nitro - and triptorelin radicals; or an aromatic five-membered a heterocycle containing one or more, identical or different heteroatoms selected among nitrogen atoms, oxygen or sulfur, and possibly substituted by one or more of the ylamino - dialkylamino-, alkoxycarbonyl-, acyl, arylcarboxylic, carboxyl, karamolegos, alkylcarboxylic, dialkylanilines or alkoxycarbonyl radicals, provided that the substituents phenyl,- or-afternova and aromatic heterocyclic radicals, the alkyl radicals and alkyl portions of other radicals contain 1-4 carbon atoms; alkeneamine and alkyline radicals contain 2 to 8 carbon atoms, and aryl radicals are phenyl or- or-raftiline radicals; and

R4means:

- linear or branched alkyl radical with 1-8 carbon atoms, a linear or branched alkanniny radical with 2-8 carbon atoms, linear or branched alkynylaryl radical with 2-8 carbon atoms, cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms or bicycloalkyl radical with 7 to 11 carbon atoms, and each of these radicals may be substituted by one or more substituents selected among halogen atoms and hydroxyl radical, alkoxyl carbon piperidino radical, morpholino radical, piperazine-1-ilen radical (possibly substituted in position 4 alkyl radical with 1-4 carbon atoms or phenylalkyl radical, the alkyl part of which contains 1-4 carbon atoms), cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms, possibly substituted phenyl radical, cyano radical, carboxyl or alkoxycarbonyl, the alkyl portion of which contains 1-4 carbon atoms;

- or aryl radical, possibly 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, karamolegos, alkylcarboxylic, dialkylanilines, cyano-, nitro-, azido-, triptorelin or triptoreline radicals;

or saturated or unsaturated 4-6 membered heterocyclyl radical, possibly substituted by one or more alkyl radicals with 1-4 of carbon atoms is a branched alkanniny radical with 2-8 carbon atoms, linear or branched alkynylaryl radical with 2-8 carbon atoms, cycloalkyl radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms or bicycloalkyl radical with 7 to 11 carbon atoms, these radicals can be substituted by one or more substituents selected among halogen atoms and hydroxyl radical, CNS radical with 1-4 carbon atoms, dialkylamino radical, each alkyl portion of which contains 1-4 carbon atoms, piperidino radical, morpholino radical, piperazine-1-ilen radical (possibly substituted in position 4 alkyl radical with 1-4 carbon atoms or phenylalkyl radical, the alkyl portion of which contains 1-4 carbon atoms), cyanoaniline radical of 3-6 carbon atoms, cycloalkenyl radical with 4 to 6 carbon atoms, possibly substituted phenyl radical, cyano radical, carboxyl or alkoxycarbonyl, the alkyl portion of which contains 1-4 carbon atoms;

provided that cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be substituted by one or more alkyl radicals with 1-4 carbon atoms

The invention relates to new compounds of General formula (I), where R1IT denotes, 0-acyl; R2denotes a group of the following formulas II, III, IV, V, VI, VII

The invention relates to new nitrates alcohols of General formula (I), where R', R", n, m are presented in the claims, the way they are received by means of nitration of 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazino

The invention relates to a new method of obtaining derivatives taxane General formula

< / BR>
which have valuable protivoanemicakimi and antitumor properties

FIELD: organic synthesis.

SUBSTANCE: invention relates to a method for preparing N-dibenzoylpaclitaxel (formula I ) via esterification of 7-protected baccatin (III) with reactive carboxylic acid derivatives of general formula II (wherein R1 is aryl or heteroaryl) and single-step removal of protecting ester groups under acid conditions. Compound I can be suitable for preparation of paclitaxel and its analogues.

EFFECT: simplified synthetic procedure.

15 cl, 7 ex

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

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new semi-synthetic taxanes of the formula (1):

wherein R and R1 can be similar or different and represent hydrogen atom (H), (C1-C18)-acyl group, benzoyl group; R2 and R3 represent hydrogen atom (H) or R2 and R3 in common form carbonate or thiocarbonate residue; R4 represents benzoyl group optionally substituted at meta-position; R' represents hydrogen atom (H) or (C1-C4)-alkyl; R'' represents (C1-C4)-alkyl or phenyl; R''' represents tert.-butoxy-group under condition that R and R1 both can't represent hydrogen atom (H). Also, invention relates to a pharmaceutical composition based on compounds of the formula (1) eliciting an anti-tumor, anti-angiogenic and anti-arthrosis effect. Invention provides preparing new compounds eliciting cytotoxicity comparable with cytotoxicity of other taxanes but showing reduced systemic toxicity that can be administrated by intravenous and oral routes.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 cl, 1 tbl, 7 ex

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