The method of obtaining taxan and an intermediate connection to receive them

 

(57) Abstract:

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV to obtain the compounds of formula V:

d) optional selective acetylation of the hydroxyl group in position 10 of the compounds of formula V with obtaining obtaining the compounds of formula I. Intermediate compounds of formula IV:

where R and R1take the values specified above. The technical result - usovershenstvany way. 2 C. and 7 C.p. f-crystals.

The present invention concerns a method of obtaining taxan from 10-deacetylbaccatin III.

Paclitaxel (paclitaxel) is a well-known anticancer drug with a structure taxane, industrial receipt of which is extremely complex.

Paclitaxel was first isolated by extraction from the bark of the trunk Taxus brevifolia, and now it is synthesized based on 10-deacetylbaccatin III, intermediate compounds present in the leaves of various species of yew tree, especially in the leaves of Taxus baccata L., thereby avoiding the environmental problems associated with the availability of the bark of T. Brevifolia.

The literature provides a number of synthetic methods: US Re. 34.277 (reissue of U.S. patent 4924011) describes poluentes of paclitaxel from 10-deacetylbaccatin III-protected hydroxyl group-7 trialkylsilyl group, in particular triethylsilane, and in position 10 acetyl group. In WO 98/08832 protection of the hydroxyl group of the C-7 is carried out using trichloroethylene gr is dctii, with a suitable derivative phenylazomethine, receiving paclitaxel after removing the protection of hydroxyl groups in position 7 and 2’ and benzoylation amine.

In WO 93/06094 receive paclitaxel interaction between connection type beta-lactam with a 7-criticallyacclaimed III. The desired product is obtained by removing the protection in an acidic environment.

In U.S. patent 5476954 synthesis of paclitaxel conduct based on 10-deacetylbaccatin III, protecting the hydroxyl-7 2,2,2-trichlorocarbanilide (Troc) and the hydroxyl-10 using the Troc or acetyl group.

It is therefore evident that the crucial stage of the synthesis of paclitaxel is selective etherification on the C-7 using easily and selectively removed group. Still 7-triethylenediamine III was considered to be the primary intermediate compound. The output shown for the conversion of 10-deacetylbaccatin III 7-triethylsilyl-10-deacetylbaccatin III, is about 85% when using from 5 to 20 moles cilleruelo agent. Output subsequent acetylation reaction, with the formation of 7-triethylenemelamine III, is about 85%.

U.S. patents 5621121 and 5637723 describe the syntheses taxan, including paclitaxel, by reacting adequately protected ¢ group replaced by alkoxygroup (U.S. patent 5621121) or trialodine groups, in particular trichlorethylene (U.S. patent 5637723), with subsequent removal of the protection by disclosing oxazolidinone rings.

Protective group, recognized as particularly suitable, include silyl, 2, 2, 2-trichlorocarbanilide or 2-(2-(trichloromethyl)propoxy) carbonyl group.

Essentially the same methods can also be used to receive docetaxel (Docetaxel), another well-known derived taxane, widely used in clinical practice.

Currently found a way of getting taxan, in particular paclitaxel and docetaxel, reaching higher outputs than the known methods.

The method according to the invention, shown on the following next the scheme includes:

a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene groups;

b) subsequent etherification of the hydroxyl in position 13 interaction with the compound of the formula (VII):

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or premenopausal selective acetylation of the hydroxyl in position 10 for such compounds, where R2means acetyl;

e) acid hydrolysis oxazolidinone rings.

The method according to the invention differs from the methods known from the prior art, so that the reaction sequence is an easier way than the above known methods, and greatly improved in respect of the resulting outputs.

Stage a) is usually done with trichloroacetic anhydride in a suitable solvent and in the presence of bases, such as pyridine, triethylamine and the like.

Substantial derivative oxazolidin-5-carboxylic acid is carried out in the presence of a condensing agent, such as dicyclohexylcarbodiimide, or other known reagents in an anhydrous organic solvent, preferably aliphatic, aromatic or chlorinated hydrocarbons, at a temperature ranging from room temperature to the boiling temperature of the solvent.

From the resulting complex ester of oxazolidine then remove protection, removing trichloroethylene groups in positions 7 and 10 treatment NH4HE/NH4C1 in aliphatic alcohols, preferably methanol.

Selective acetylation of the hydroxyl is barely, such as tetrahydrofuran, dichloromethane, ethyl acetate, in the temperature range 5 to 40C.

Treatment with organic or inorganic acids in solvents such as methanol, ethanol, tetrahydrofuran, at temperatures about in the range from -2 to +2C, gives the required derivatives taxane. The use of formic acid in tetrahydrofuran at a temperature of 0C is particularly preferable.

Intermediate compounds of oxazolidine are known or can be obtained by known methods by the interaction of ester azaserine with 4-methoxybenzaldehyde.

It is proved that the choice of anisic aldehyde is particularly important for the formation of oxazolidine because oxazolidinone acid, in contrast to the methods described in U.S. patent 5621121, 5637723 (Rhone-Poulenc Rorer) and 5821363 (Up John), can be easily bicrystalline and brought to the isomer ratio of 95:5, which is extremely helpful and beneficial to the subsequent stage. In addition, oxazolidinecarboxylate acid obtained from anise aldehyde, particularly stable during unprotect trichloroacetic ether and subsequent stage acetylation. In these conditions, 2,4-dimethoxybenzaldehyde, used in Pat is quite stable.

The method according to the invention, in addition to paclitaxel (R - benzoyl, R1- phenyl) and docetaxel (R - tert-butoxycarbonyl, R1- phenyl), allows for efficient and convenient to get other derivatives taxane.

The compounds of formula IV have not been previously described and therefore constitute an additional object of the invention as intermediates used in the synthesis of derivatives taxane.

The following examples illustrate the invention in more detail.

Example 1. Getting 7,10-bis-trichloroacetyl-10-deacetylbaccatin III.

A solution of 10 g of 10-deacetylbaccatin III (18.4 mmol) in 125 ml dry methylene chloride and 42 ml of pyridine is added dropwise to 4,77 ml of trichloroacetic anhydride (42,32 mmol). The reaction mixture is stirred for three hours or at least until the end of the reaction is controlled by TLC on silica gel using a mixture of 5:5 n-hexane/ethyl acetate as eluent. After completion of the reaction, add 5 ml of methanol to decompose excess trichloroacetic anhydride, and then the water. The organic phase is washed thoroughly with model HC1 (0.1 M solution in water) to remove pyridine, after which the remaining organic phase is dried over MgSO4and concentrate to dryness in a vacuum. Paul is the cue and spectroscopic characterization of:

IR (R) 3517, 1771, 1728, 1240, 981, 819, 787, 675 cm-1;

1H-NMR (200 MHz); 8,11 (Bz, AA’), 7,58 (Bz), 7,46 (Bz, BB’), 6,50 (c, H-10), 5,72 (m, N-N-2), 5,02 (d, J=8 Hz, H-5), of 4.95 (m, H-13), 4,37 (d, J=8 Hz, H-20A), 4,18 (d, J=8 Hz, H-20b), was 4.02 (d, J=6 Hz, H-3), 2,32 (4-AC), 2,22 (s, H-18), at 1.91 (s, H-19), and 1,25 1,11 (s, H-16, H-17), so pl.=172-S, []D=-36 (Meon, With Or=0.6).

Example 2. 13-(2-(4-methoxyphenyl)-N-benzoyl-4-phenyloxazolidine)-10-deacetylbaccatin III.

17 g 7,10-bistricioarei-10-deacetylbaccatin III is dissolved in 250 ml of anhydrous toluene and added dropwise with stirring to the 12.6 g of 2-(4-methoxyphenyl)-N-benzoyl-4-phenyloxazolidine-5-carboxylic acid and 6 g of DCC (dicyclohexylcarbodiimide). After stirring overnight at 40°C. the reaction mixture was filtered and concentrated to dryness. The residue is dissolved in 300 ml of methanol/tetrahydrofuran and added to 24 ml of 2 M aqueous solution of NH3. After 1.5 hours at room temperature, the reaction mixture was concentrated to small volume under vacuum, then diluted with water and the entire amount received is extracted with ethyl acetate. The extract was concentrated to dryness, and the residue is purified on a column of silica gel, elwira product with a mixture of ethyl acetate/petroleum ether 1:1, receiving 16,8 g specified in the title of the product so pl. S and []D=-58 (Meon, actor of 13.7 g of product from example 2 in 200 ml of tetrahydrofuran is added to 56 ml of 10% suspension l3.7H2About in tetrahydrofuran followed by the addition of 5.5 ml uxusnuu anhydride. After stirring over night at room temperature the reaction mixture is filtered, the filtrate is treated with methanol and concentrated to small volume, the mixture is diluted with N2O and the product extracted with ethyl acetate, receiving 12 g(84%) 13-(2-(4-methoxybenzylidene)-N-benzoyl-4-phenyloxazolidine)-baccatin III having the following chemical and spectroscopic characteristics:

1H-NMR: 8,07 (e, BZ), 7,60-7,19 (m, aromatic), of 7.48-6,90 (AA', BB', n-h), 6,33 (s, H-10), 5,67 (d, J=5 Hz, H-2), 5.56mm (ush.s, H-3'), is 4.93 (d, J=8 Hz, H-5), 4,90 (ush.s, H-2'), of 4.45 (m, H-7), 4,28 (d, J=8 Hz, H-20A), to 4.16 (d, J=8 Hz, H-20b), 3,82 (s, ome), and 2.27 (s, AC), 2,08 (SLA), of 1.66 (s, H-19), 1,29 is 1.16 (s, H-16, H-17), so pl. 146S, []D=-62 (Meon, S=0,8).

Example 4. Receiving paclitaxel.

12 g of 13-(2-(4-methoxyphenyl)-N-benzoyl-4-phenyloxazolidine)-baccatin III is dissolved in 50 ml of tetrahydrofuran, at 0 ° C add 5 ml of formic acid; the reaction mixture is allowed to mix at 0°C for three hours, then diluted with water; formic acid to neutralize knso3and the suspension is re-extracted with ethyl acetate. An ethyl acetate extracts washed with water and concentrated to small volume. PEFC is an economic characteristics of which correspond to those indicated in the literature.

Example 5. Receiving docetaxel.

17 g 7,10-bistricioarei-10-deacetylbaccatin III is dissolved in 250 ml of anhydrous toluene and added dropwise with stirring to 11.6 g of 2-(4-methoxyphenyl)-N-tert-butoxycarbonyl-4-phenyloxazolidine-5-carboxylic acid and 6 g of DCC. After stirring overnight at 40 ° C, the reaction mixture was filtered and concentrated to dryness. The residue is dissolved in 300 ml of methanol/tetrahydrofuran and added to 24 ml of 2 M aqueous solution of NH3. After 1.5 hours at room temperature, the reaction mixture was concentrated to small volume under vacuum, then diluted with water and the entire amount received is extracted with ethyl acetate. The extract was concentrated to dryness and 10 grams of the specified residue is dissolved in THF and added dropwise at 0C to 5 ml of formic acid. The reaction mixture was allowed to mix at 0C for three hours, then diluted with water; formic acid to neutralize knso3and the suspension is extracted several times with ethyl acetate. The organic extracts washed with water and concentrated to small volume. After crystallization from the same solvent gain of 9.2 g of docetaxel, physico-chemical and spectroscopic characteristics of which correspond to those indicated in the literature.

R1means phenyl or a straight or branched alkyl or alkenyl;

R2means hydrogen or acetyl, which comprises (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid;

R1means phenyl or a straight or branched alkyl or alkenyl,

obtaining the compounds of formula IV

(C) removing trichloroethylene protective groups of the compounds of formula IV to obtain the compounds of formula V

d) optional selective acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI

e) acid hydrolysis oxazolidinone ring compounds of the formula VI with obtaining connection Faure is P CLASS="ptx2">

3. The method according to p. 2, where the condensing agent is dicyclohexylcarbodiimide, and the base is pyridine.

4. The method according to any of the preceding paragraphs, where trichloroethylene groups in positions 7 and 10 are removed by the processing of NH4OH/NH4Cl in aliphatic solvents.

5. The method according to any of the preceding paragraphs, where the selective acetylation at the stage d) is carried interaction with acetic anhydride in the presence of salts of cerium III, scandium or ytterbium.

6. The method according to any of the preceding paragraphs, where stage e) is carried out by treatment with organic or inorganic acids to aliphatic alcohols or tetrahydrofuran.

7. The method according to p. 6, where the hydrolysis is carried out with formic acid.

8. The method according to any of the preceding paragraphs to obtain paclitaxel (R - benzoyl, R1- phenyl, R2- acetyl) or docetaxel (R - tert-butoxycarbonyl, R1- phenyl, R2- N).

9. Intermediate compounds of formula IV

where R and R1take the values specified in paragraph 1.

 

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< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

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< / BR>
where a represents a group

< / BR>
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< / BR>
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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

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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