Method for preparing derivatives of baccatin iii

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a novel method for preparing 14β-hydroxy-1,4-carbonate-desacetylbaccatin III and intermediate substances used in preparing new derivatives of taxane and possessing an antitumor activity. Method involves the following stages: a) protection of hydroxyls at positions 7 and 10 in 10-desacetylbaccatin III wherein R and R1 are taken among hydrogen atom, (C1-C10)-alkyl or aryl, (C1-C10)-alkyl- or aryl-carbonyl, trichloroacetyl, (C1-C4)-trialkylsilyl; preferably, when R and R1 are similar then they represent trichloroacetyl; when they are different then, preferably, R represents trichloroacetyl and R1 represents acetyl; or R represents triethyl or trimethylsilyl and R1 represents acetyl; b) two-stage oxidation to yield a derivative oxidized to carbonyl at position 13 and hydroxylated at position 14; c) carboxylation of vicinal hydroxyls at positions 1 and 14 to yield 1,14-carbonate derivative; d) reduction of carbonyl at position 13; e) removal of protective groups at positions 7 and 10. Also, invention relates to intermediate substances. Invention provides preparing intermediate substances used in synthesis of taxane.

EFFECT: improved preparing method.

8 cl, 8 ex

 

The present invention relates to new intermediate products used in the synthesis of derivatives of 14β-hydroxy-1,14-carbonate-deacetylbaccatin III and to methods for their preparation. Intermediate compounds obtained by the method according to this invention, can be used to obtain new derivatives taxane with antitumor activity.

Taxanes represent one of the most important classes of anticancer agents developed in recent years. Paclitaxel is a complex diterpene isolated from the bark of Taxus brevifolia and is regarded as a "lead compound" for cancer treatment. Currently there is an intensive search of derivative taxane with a higher therapeutic activity and improved pharmacokinetic profile. Specific products belong to derived baccatin III, modified in various ways in relation to the main structure. Examples of these compounds are derivatives of 14β-hydroxy-baccatin III, described in US 5705508, WO 97/43291, WO 96/36622. At the present time derivative 14β-hydroxy-1,14-carbonate-deacetylbaccatin III is obtained from its predecessor 14β-hydroxy-deacetylbaccatin III, which is a natural compound produced in small quantities by extraction from the leaves of Taxus wallichiana, as described in EP all a great need for new intermediate compounds or widely used alternative methods, which allow you to simply and efficiently find the derivatives of 14β-hydroxy-1,14-carbonate-deacetylbaccatin III.

Currently, found that 14β-hydroxy-1,14-carbonate-deacetylbaccatin III can be obtained by the method using 10-deacetylbaccatin III as a starting compound, which, in contrast to 14β-hydroxy-baccatin III, can be easily isolated in large quantities from the leaves of Taxus baccata.

Thus, the present invention relates to a method for 14β-hydroxy-1,14-carbonate-deacetylbaccatin III, comprising the following stages:

1) protection of the hydroxy groups in positions 7 and 10 10-deacetylbaccatin III

where R and R1selected from hydrogen, C1-C10the alkyl or aryl, With1-C10alkyl - or aryl-carbonyl, trichloroacetyl,1-C4trialkylsilyl; preferably, when R and R1the same, they are trichloroacetyl, whereas, when they are different, preferably R is trichloroacetyl and R1is acetyl, or R is triethyl or trimethylsilyl and R1represents acetyl;

2) two-stage oxidation with derivatization, oxidized in position 13 gidrauxilirovannogo in position 14

3) carboxylation vicina is lnyh hydroxyl in positions 1 and 14 with getting 1,14-carbonate derivative

4) recovery of the carbonyl in position 13

5) removing the protective groups in positions 7 and 10

Ways of protecting hydroxyl at positions 7 and 10 described in Holton et al., Tetrahedron Letters 39 (1998), 2883-2886. Selective protection of the hydroxyl source connection deacetylbaccatin III possible due to their different reactivity. In particular, it is found that the reactivity towards allermuir, alkylating or silylium agents varies in the order C(7)-OH>C(10)-OH>C(13)-OH>C(1)-OH, so groups in positions 7 and 10 can be selectively protected, whereas the hydroxyl in positions 1 and 13 can remain free.

In addition, by changing the reaction conditions it is possible to completely change the order of reaction of the hydroxyl in positions 7 and 10, allowing, thus, their different substitution. Examples of reagents and reaction conditions used in the protection of the hydroxyl in position 10 and 7, described in the publications cited above.

Stage oxidation of the hydroxyl in position 13 using dioxide, magnesium dioxide or bismuth in a solvent selected from acetonitrile, acetone or a mixture of 9:1 ethyl acetate/methylene chloride, with vigorous stirring, preferably with the of oxida magnesium in acetonitrile or acetone. The reaction proceeds rapidly with the formation of a derivative, oxidized at position 13, which may be isolated from the reaction medium, whereas a longer interaction network derived oxidized in position 13 and gidrauxilirovanne in position 14.

The next stage carboxylation of hydroxyl in positions 1 and 14 is usually performed with the use of phosgene or triphosgene in a mixture of methylene chloride/toluene in the presence of pyridine. Then received 1,14-carbonate derivative can be easily restored in position 13 with the formation of the corresponding 13-hydroxy. The specified recovery is regioselective on the carbonyl in position 13, whereas the carbonyl in position 9 remains neizmenennymi, and stereoselective, almost exclusively giving 13-α isomer. This reaction is usually carried out using sodium borohydride in methanol and achieve high outputs. The last stage is the removal of the protective groups of the hydroxyl in positions 7 and 10 with the final product 14β-hydroxy-1,14-carbonate-deacetylbaccatin III. Conditions and reagents that can be used for selective removal of the protective groups of the hydroxyl in position 7 and 10, described by Zheng et al., Tetrahedron Lett., 1995, 36, 2001, and Datta et al., J. Org. Chem., 1995, 60, 761. The final product is an extremely the useful intermediate compound for the synthesis of various derivatives taxane. As indicated above, this intermediate connection so far has been based on 14β-hydroxy-baccatin III, extracted from the leaves of Taxus wallichiana with low outputs. The method according to the present invention allows to obtain the same intermediate compounds in high yields based on the connections available in large quantities. Examples of compounds with antitumor activity, which can be obtained on the basis of 14β-hydroxy-1,14-carbonate deacetylbaccatin III, presents US 5705508, WO 97/43291, WO 96/36622.

In accordance with the preferred implementation of the method according to the present invention deacetylbaccatin III is subjected to interaction with trichloroacetamido in methylene chloride in the presence of triethylamine and using N,N-dimethylaminopyridine (DMAP) in catalytic amounts. It was found that the use of trichloracetate as a protective group in the oxidation, carboxylation and the recovery is very convenient in accordance with the method according to this invention. In particular, the derived 7,10-bistrilitsa obtained with a quantitative yield of the parent compound, after oxidation and carboxylation is easily restored in position 13 with simultaneous removal of the protective trichloracetate groups receiving 14β-hydroxy-1,14-carbonate-deacetylbaccatin III. COI is the whether DMAP in catalytic quantities provides certain advantages from the point of view of industry and the environment, taking into account the fact that until now, the acylation of the substrate was carried out in pyridine and subsequent problems draining the remaining solvent.

The following intermediate compounds obtained in accordance with the preferred implementation described above, are part of the present invention.

The following examples illustrate the invention in more detail.

Example I

Getting 7,10-bistricioarei-10-deacetylbaccatin III

The first option

of 4.77 ml of trichloroacetic acid anhydride (42,32 mmol) is added dropwise to a solution of 10 g of 10-deacetylbaccatin III (18.4 mmol) in 125 ml dry methylene chloride and 42 ml of pyridine. The reaction mixture is stirred for three hours or until completion of the reaction, controlling by means of thin layer chromatography (TLC) on silica gel using as eluent a mixture of 1:1 n-hexane/ethyl acetate. After completion of the reaction, add 5 ml of methanol to decompose excess anhydride trichloroacetic acid, then add water. The organic phase is thoroughly washed with acidified (HCl) with water to remove pyridine, while the remaining organic phase is dried over MgSO4and concentrated to dryness in vacuo to obtain a pale yellow solid (17 g), which crystallized from chloroform, [α]D -34° (CH2Cl2C to 5.8). IR (KBr): 3517, 1771, 1728, 1240, 981, 819, 787, 675 cm-1;

1H-NMR (200 MHz): δ 8,11 (Bz C), 7,46 (Bz, BB'), 6,50 (s, H-10), 5,72 (m, H-7, H-29), 5,02 (d, J=8 Hz, H-5), 4,95 (8m, 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), was 1.94 (m, H-14α), 1,89 (m, H-14β).

The second option

10-Deacetylbaccatin III (10 g, 18,38 mmol) suspended in CH2Cl2(120 ml), add DMAP (220 mg, 1.4 mmol, 0.1 EQ.) and cooled to 0°C in an ice bath. Add Et3N (10,26 ml, 73,6 mmol, 4 equiv.) and immediately after this Cl3CCOCl (4,12 ml, to 36.8 mmol, 2 EQ.) in a stream of nitrogen for 5 min, maintaining the temperature below 10°C. After complete addition, the mixture is left to mix in an ice bath for 15 minutes, then leave bath and the reaction mixture was stirred at room temperature for 1 h After 1 h the reaction mixture was analyzed by TLC (AcOEt 2/n-hexane 3, Rf 10-DAB III=0,05, Rf 7,10-bistricioarei-10-DAB III=0.26) and added Cl3CCOCl (1 ml, 0.5 EQ.). Stirring is continued at room temperature for 10 min, then the reaction mixture was poured in chemical beaker containing 160 g of crushed ice and left under stirring until the establishment of the equilibrium state at room temperature (about 1 hour). Then separated from the aqueous phase and extracted with CH2Cl2(3×40 ml). United'or is adicheskie phases are washed with 1 N. HCl (20 ml), then with saturated solution of NaHCO3(20 ml), dried over Na2SO4and the solvent is evaporated. Weight of the crude product of 16.5, After crystallization from chloroform IR,1H-NMR and [α]Dthe spectra are consistent with those obtained for compounds using pyridine anhydride and trichloroacetic acid.

Example II

Oxidation at position 13 and hydroxylation at position 14 7,10-bistrilitsa 10-deacetylbaccatin III

30 g of activated MnO2added to a solution of 7,10-bistrilitsa 10-deacetylbaccatin III (3 g) in acetonitrile (40 ml), stirred suspension of magnetic stirrer at room temperature and monitored the progress of the reaction by TLC (mixture of petroleum ether-ethyl acetate 5:5; Rf feedstock of about 0.31 in). After about one hour completed 13-dehydrofreezing (TLC analysis, Rf 13-dehydrofreezing about 0,50). Then stirring is continued for about 72 hours, during this time 13-dihydroprogesterone slowly oxidized to 14β-hydroxy (Rf approximately 0,36). The reaction mixture was filtered through celite and the residue repeatedly washed with ethyl acetate. The solvent is evaporated and the residue purified column chromatography on silica gel (100 ml, eluent is a mixture of petroleum ether-ethyl acetate 7:3) what rucenim 170 mg 13-dehydrofreezing and of 2.38 g 14β -hydroxy-13-dehydrofreezing.

13 Dehydro-14β-hydroxy-10-deacetylbaccatin III, 7,10-bistricioara, white powder, so pl. 97°C. IR (KBr disk): 3440, 1780, 1767, 1736, 1686, 1267, 1232, 1103, 1010, 854 cm-1;

1H-NMR (200 MHz, CDCl3): δ 8,07 (Bz AA'), 7,60 (Bz, C), 7,49 (Bz, BB'), 6,52 (c, H-10), of 5.92 (d, J=6,7 Hz, H-2), 5,70 (user. t, J=8.0 Hz, H-7), 4,95 (user. d, J=8,2 Hz, H-5), 4,37 (d, J=8,2 Hz, H-20a), or 4.31 (d, J=8,2 Hz, H-20b), 4,17 (s, H14), was 4.02 (d, J=6,7 Hz, H-3), a 2.71 (m, H-6), to 2.29 (s, OAc), 2,17 (s, OAc), a 1.96 (s, H-18), 1,27, 1,01 (s, H-16, H-17 and H-19).

Example III

Oxidation/hydroxylation of 7-triethylenemelamine III

10 g of activated MnO2added to a solution of 7-triethylenemelamine III (1.0 g) in acetonitrile (10 ml), stirred suspension of magnetic stirrer at room temperature and monitored the progress of the reaction by TLC (mix 6:4 petroleum ether-ethyl acetate; Rf feedstock approximately 0.25 in). After about two hours completed 13-dehydrofreezing (TLC analysis, Rf 13-dehydrofreezing approximately 0,45). Then continue mixing for approximately 188 hours, in the process, add another MnO2(10 g). 13-Dihydroprogesterone slowly oxidized to, respectively, 14β-hydroxy (Rf approximately 0,38). The reaction mixture was filtered through celite and the residue washed with ethyl acetate. The solvent is evaporated and the residue purified column chromatography on silica gel (40 ml, alue the t - a mixture of 7:3 petroleum ether-ethyl acetate) to give 126 mg of 13-dehydrofreezing, 479 mg (46%) 14β-hydroxy-13-dehydrofreezing and 189 mg mixtures thereof. 13 Dihydro-7-triethylcitrate III, white powder, so pl. 168°C [α]D25-35 (CH2Cl2C 0,67). IR (KBr): 3488, 1726, 1711, 1676, 1373, 1269, 1244, 1230, 1105 cm-1.1H-NMR (200 MHz, CDCl3): δ 8,07 (Bz AA'), 7,60 (Bz, C), 7,49 (Bz, BB'), 6,59 (c, H-10), 5,69 (d, J=6,9 Hz, H-2), to 4.92 (d, J=8,2 Hz, H-5), 4,48 (DD, J=a 10.6 Hz, H-7), to 4.33 (d, J=8.0 Hz, H-20a), of 4.12 (d, J=8,0 Hz, H-20b), 3,91, (d, J=6,9 Hz, H-3), 2,96 (d, J=20 Hz, H-14a), 2,65 (d, J=20 Hz, H-20b), 2,50 (m, H-6α), 2,23 (c, OAc), 2,19 (c, OAc + H-18), 1,67, 1,28, 1,19 (c, H-16, H-17 and H-19), 0,19 (m, TES).

13 Dehydro-14β-hydroxy-10-deacetylbaccatin III, 7,10-bistricioara, white powder, so pl. 153°C [α]D25+20 (CH2Cl2C 0,75). IR (KBr): 3431, 1723, 1692, 1371, 1269, 1242, 1223, 1096 cm-1.1H-NMR (500 MHz, CDCl3): δ 8,06 (Bz AA'), 7,60 (Bz, C)of 7.48 (Bz, BB'), 6,51 (c, H-10), 5,88 (d, J=6,9 Hz, H-2), the 4.90 (d, J=8,2 Hz, H-5), 4,47 (DD, J=10,67 Hz, H-7), 4,30 (d, J=8 Hz, H-20a), 4,28 (d, J=8,2 Hz, H-20b), 4,13 (user. d, J=2 Hz, H-14), of 3.84 (d, J=6,9 Hz, H-3), 3,69 (user. d, J=2 Hz, 14-OH), 3,62 (c, 1-OH), 2,52 (m, H-6α), 2,24 (c, OAc), 2,21 (c, OAc), 2,11 (c, H-18), with 1.92 (m, H-6β), 1,74, 1,56, 1,28 (c, H-16, H-17 and H-19), were 0.94 (m, TES), 0,59 (m, TES). HRNS: 714,3092 (calculated for C37H50O12Si 714,3092).

Example IV

Oxidation/hydroxylation of 7-triethylenemelamine III

10 g of activated MnO2added to a solution of 7-triethylenemelamine III (1.0 g) in acetonitrile 10 ml), stirred at room temperature and monitored the progress of the reaction by TLC (mixture of petroleum ether-ethyl acetate 6:4; Rf feedstock approximately 0.25 in). After about two hours completed 13-dehydrofreezing (TLC analysis, Rf 13-dehydrofreezing approximately 0,45). Then continue stirring for approximately 188 hours, during which adds another MnO2(10 g). 13-Dihydroprogesterone slowly oxidized to, respectively, 14β-hydroxy (Rf approximately 0,38). The reaction mixture was filtered through celite and the residue washed with ethyl acetate. The solvent is evaporated and the residue purified column chromatography on silica gel (40 ml, eluent a mixture of 7:3 petroleum ether-ethyl acetate) to give 126 mg of 13-dehydrofreezing, 479 mg (46%) 14β-hydroxy-13-dehydrofreezing and 189 mg mixtures thereof.

13 Dihydro-7-triethylcitrate III, white powder, so pl. 210°C [α]D25-48 (CH2Cl2C 0,50). IR (KBr): 3478, 1728, 1676, 1373, 1271, 1240, 1071, 1026 cm-1.1H-NMR (200 MHz, CDCl3): δ 8,07 (Bz AA'), to 7.64 (Bz, C), 7,50 (Bz, BB'), 6,46 (c, H-10), 5,70 (d, J=6,9 Hz, H-2), of 4.95 (d, J=8,2 Hz, H-5), 4,51 (DD, J=10,7 Hz, H-7), 4,32 (d, J=8,4 Hz, H-20a), 4,14 (d, J=8.4 and Hz, H-20b), 3,92, (d, J=6,9 Hz, H-3), 2,99 (d, J=20 Hz, H-14a), 2,68 (d, J=20 Hz, H-14b), of 2.56 (m, H-6α), 2,29 (c, OAc), 2,18 (c, OAc), 2,08 (c, H-18), 1,68, 1,29, 1,20 (c, H-16,H-17 and H-19), 0,19.

13 Dehydro-14β-hydroxy-7-triethylcitrate III, white powder, TPL 220°C [α]D25+19 (CH2Cl2C 0,42). IR (KBr): 3568, 1710, 1719, 1686, 1372, 1282, 1240, 1219, 1073 cm-1.1H-NMR (200 MHz, CDCl3): δ 8,09 (Bz AA'), 7,60 (Bz, C), 7,51 (Bz, BB'), 6,39 (c, H-10), of 5.89 (d, J=6,9 Hz, H-2), 4,94 (d, J=8,2 Hz, H-5), 4,47 (DD, J=10,7 Hz, H-7), or 4.31 (user. c-H-20a + H-20b), 4,15 (c, H-14), of 3.69 (d, J=6,9 Hz, H-3), 2,29 (c, OAc), 2,16 (c, H-18), and 2.14 (c, OAc), 1,74, 1,21, 1,10 (c, H-16, H-17 and H-19). HRMS: 600,6112 0,19 (calculated for C31H36O12Si 600,6103).

Example V

Getting 1,14-carbonate-13-degidro-7-TES-baccatin III

A solution of 13-degidro-14β-hydroxy-7-triethylenemelamine III (124 mg, 1,17 mmol) in CH2Cl2(1 ml) and pyridine (of 0.56 ml, 6.8 mmol, 20 mol equiv.) added dropwise over 5 min to a solution of phosgene (1.8 ml, 20% solution in toluene, 3.4 mmol, 20 mol equiv.) in CH2Cl2(2 ml). The mixture is stirred at room temperature for 1 hour and then the excess phosgene is neutralized with saturated solution of NaHCO3and extracted with CH2Cl2. The organic phase is washed with a saturated solution of NaHCO3saturated salt solution and dried (Na2SO4). The solvent is evaporated to obtain a reddish residue, which is purified on a small column of silica gel (about 5 ml, eluent - hexane/ethyl acetate 8:2) to give 118 mg (92%) of carbonate. In the case when the reaction is carried out with triethylamine as the base without reverse add, get a mixture of 1,14-to the of rbonate and 2-Dibenzoyl-1,2-carbonate-14 benzoate (about 1:15).

13 Dehydro-14β-hydroxy-7-triethylcitrate III 1,14-carbonate, white powder, so pl. 153°C [α]D25+23 (CH2Cl2C 0,75). IR (KBr): No. of lanes OH 1834, 1734, 1709, 1373, 1242, 1225, 1088, 1057 cm-1.1H-NMR (200 MHz, CDCl3): δ 7,99 (Bz AA'), 7,60 (Bz, C)of 7.48 (Bz, BB'), 6,51 (c, H-10), 6,12 (d, J=6,9 Hz, H-2), the 4.90 (d, J=8,2 Hz, H-5), 4,78 (c, H-14), of 4.44 (DD, J=10,7 Hz, H-7), 4,34 (d, J=8 Hz, H-20a), 4,19 (d, J=8,2 Hz, H-20b), 3,80 (d, J=6,9 Hz, H-3), of 2.50 (m, H-6α), 2,23 (c, OAc), 2,22 (c, OAc), 2,19 (c, H-18), with 1.92 (m, H-6β), 1,72, 1,39, 1,26 (c-H-16, H-17 and H-19), of 0.90 (m, TES), of 0.56 (m, TES). HRNS: 740,2851 (calculated for C38H48O13Si 740, 2864).

13 Dehydro-14β-hydroxyacetic III 1,14-carbonate, white powder, 240°C [α]D25a-2.5 (CH2Cl2C 0,4). IR (KBr): 3539, 1831, 1736, 1240, 1088, 1068, 1057, 1024 cm-1.1H-NMR (200 MHz, CDCl3): δ 7,98 (Bz AA'), to 7.61 (Bz, C), 7,50 (Bz, BB'), 6,39 (c, H-10), 6,14 (d, J=6,9 Hz, H-2), to 4.98 (d, J=8,2 Hz, H-5), 4,80 (c, H-14), 4,43 (DD, J=10,7 Hz, H-7), 4,35 (d, J=8 Hz, H-20a), 4,24 (d, J=8,2 Hz, H-20b), 3,80 (d, J=6,9 Hz, H-3), of 2.50 (m, H-6α), 2,30 (c, OAc), 2,20 (c, OAc), 2,15 (c, H-18), 1,90 (m, H-6β), 1,74, 1,34, 1,25 (c, H-16, H-17 and H-19). HRMS: 626,2005 (calculated for C33H34About1626,1999).

Example VI

Getting 1,14-carbonate-7-O-triethylenemelamine III

Excess NaBH4(about 20 mg) is added in small portions to a solution of 13-degidro-14β-hydroxy-7-triethylcitrate III 1,14-carbonate (50 mg) in methanol (5 ml). After 30 minutes add in the reaction mixture is saturated NH4Cl, extragere what acetate, washed with brine, dried over Na2SO4and remove the solvent to obtain a residue, which was purified column chromatography on silica gel (approximately 5 ml, elution with hexane-ethyl acetate 8:2) to obtain 35 mg 13α-hydroxy and 9 mg 13β-hydroxy.

14β-Hydroxy-7-triethylcitrate III 1,14-carbonate, [α]D25-35 (CH2Cl2C 0,60). IR (KBr): 3054, 1819, 1736, 1603, 1371, 1261, 1238, 1090, 1069 cm-1.1H-NMR (200 MHz, CDCl3): δ 8,06 (Bz AA'), 7,65 (Bz, C), 7,50 (Bz, BB'), 6,47 (c, H-10), 6,12 (d, J=6,9 Hz, H-2), of 5.05 (user. d, J=5.5 Hz, H-13), to 4.98 (user. d, J=9 Hz, H-5), a 4.83 (d, J=5 Hz, H-14), 4,50 (DD, J=10,7 Hz, H-7), 4,34 (d, J=8 Hz, H-20a), to 4.23 (d, J=8 Hz, H-20b in), 3.75 (d, J=6,9 Hz, H-3), of 2.56 (m, H-6α), 2,34 (c, OAc), 2,22 (c, OAc), of 1.78 (m, H-6β), 1,35 (c, H-18), 1,75, 1,18, 0,95 (c, H-16, H-17 and H-19), of 0.90 (m, TES), and 0.62 (m, TES).

14β-Hydroxy-7-triethylsilyl-13-epibatidine III 1,14-carbonate, non-crystalline, [α]D25-13 (CH2Cl2C 0,60). IR (KBr): 3630, 1825, 1734, 1603, 1375, 1262, 1091, 1071, 1049 cm-1.1H-NMR (200 MHz, CDCl3): δ 8,01 (Bz AA'), 7,63 (Bz, C)of 7.48 (Bz, BB'), 6,44 (c, H-10), 6,12 (d, J=7.2 Hz, H-2), 4,90 (user. d, J=9 Hz, H-5), to 4.81 (d, J=8 Hz, H-14), 4,48 (user., J=8, H-13), 4,50 (DD, J=10, 7 Hz, H-7), to 4.41 (d, J=8 Hz, H-20a), or 4.31 (d, J=8 Hz, H-20b), 3,68 (d, J=7.2 Hz, H-3), 2,60 (m, H-6α), 2,32 (c, OAc), and 2.26 (c, H-18), 2,21 (c, OAc), of 1.80 (m, H-6β), 1,72, 1,43, 1.27mm (c, H-16, H-17 and H-19), of 0.93 (m, TES), and 0.61 (m, TES).

Example VII

13-degidro-14β-hydroxy-7,10-bestreplicawatches the III 1,14-carbonate

To a solution of 13-degidro-14β-hydroxy-7,10-bestreplicawatches III (200 mg) in CH2Cl2(2 ml) and pyridine (1,12 ml, 20 equiv.) added dropwise within 5 min a solution of phosgene (20% in toluene, 3.6 ml, 20 equiv.) in CH2Cl2(2 ml). The mixture is stirred at room temperature for 1 h, then neutralized with excess phosgene with saturated solution of NaHCO3(3 ml). The mixture is extracted with CH2Cl2, the organic phase is washed with a saturated solution of NaHCO3then a saturated solution of NaCl and dried over Na2SO4. After removal of solvent the residue is purified column chromatography on silica gel (eluent - hexane/ AcOEt 9:1) to give 175 mg(89%) of carbonate.

13 Dehydro-14β-hydroxy-7,10-bestreplicawatches III 1,14-carbonate, a white solid non-crystalline substance. IR (KBr): 1834, 1771, 1735, 1709, 1232, 1103, 1010, 854 cm-1.

1H-NMR (200 MHz, CDCl3): δ 8,03 (Bz AA'), 7,60 (Bz, C), 7,50 (Bz, BB'), 6,52 (c, H-10), of 5.92 (d, J=6,7 Hz, H-2), 5,70 (user. t, J=8.0 Hz, H-7), 4,95 (user. d, J=8,2 Hz, H-20b), 4,77 (c, H-14), was 4.02 (d, J=6,7 Hz, H-3), a 2.71 (m, H-6), 2,29 (c, OAc), 1,96 (c, H-18), 1,27-a 1.01 (m, H-16, H-17, H-19).

Example VIII

Getting 14β-hydroxy-10-deacetylbaccatin III 1,14-carbonate

A solution of 13-degidro-14β-hydroxy-7,10-bestreplicawatches III 1,14-carbonate (500 mg) in MeOH (8 ml) cooled to 0°C in an ice bath and within 5 min to it add solid NaBH4(44 mg). The mixture plumage is eshivot at room temperature for 1 h then cooled to 0° C. for 5 min add acetone (2 ml), the mixture is concentrated and then added AcOEt (10 ml) and filtered through celite. Clean the solution washed with saturated NaCl solution and dried over Na2SO4. The solvent is evaporated to obtain a residue (a 4.5:1 mixture of epimeres C13), which is purified column chromatography on silica gel (eluent - hexane/AcOEt 1:1) to give 251 mg 13β ephemera and 55 mg 13α epimer (88%) of the carbonate with the remote protective group.

13α-14β-Hydroxy-10-deacetylbaccatin III 1,14-carbonate, non-crystalline white solid. IR (KBr): 3520 (OH), 1834, 1709,1232, 1103, 1010, 854 cm-1.

1H-NMR (200 MHz, CDCl3): δ 8,03 (Bz AA'), 7,60 (Bz, C), 7,50 (Bz, BB'), 6,27 (c, H-10), of 5.92 (d, J=6,7 Hz, H-2), 4,95 (user. d, J=8,2 Hz, H-20b), is 4.85 (m, H-13), 4,77 (c, H-14), 4,42 (user. t, J=8.0 Hz, H-7), was 4.02 (d, J=6,7 Hz, H-3), a 2.71 (m, H-6), 2,29 (c, OAc), 1,96 (c, H-18), 1,27-a 1.01 (m, H-16, H-17, H-19).

13α-14β-Hydroxy-10-deacetylbaccatin III 1,14-carbonate, non-crystalline white solid. IR (KBr): 3520 (OH), 1834, 1709, 1232, 1103, 1010, 854 cm-1.

1H-NMR (200 MHz, CDCl3): δ 8,03 (Bz AA'), 7,60 (Bz, C), 7,50 (Bz, BB'), 6,27 (c, H-10), of 5.92 (d, J=6,7 Hz, H-2), 4,95 (user. d, J=8,2 Hz, H-20b), 4,80 (m, H-13), 4,77 (c, H-14), 4,42 (user. t, J=8.0 Hz, H-7), was 4.02 (d, J=6,7 Hz, H-3), a 2.71 (m, H-6), 2,29 (c, OAc), 1,96 (c, H-18), 1,27 - a 1.01 (m, H-16, H-17, H-19).

1. The method of obtaining 14βhydroxy-1,14-carbonate-deacetylbaccatin III, comprising the following stages:

a. protection of the hydroxyl in the alogene 7 and 10 10-deacetylbaccatin III:

where R and R1selected from hydrogen, C1-C10the alkyl or aryl, With1-C10alkyl - or aryl-carbonyl, trichloroacetyl,1-C4trialkylsilyl; preferably, when R and R1the same, they are trichloroacetyl, whereas, when they are different, preferably, R represents trichloracetic and R1represents acetyl, or R represents triethyl or trimethylsilyl and R1represents acetyl;

b. the two-stage oxidation with derivatization, oxidized to the carbonyl in position 13 and gidrauxilirovannogo in position 14:

C. the carboxylation vicinal hydroxyl in positions 1 and 14 with getting 1,14-carbonate derivative:

d. the recovery of the carbonyl in position 13:

E. remove protective groups in positions 7 and 10:

2. The method according to claim 1, where R and R1the same and represent trichloroacetyl, or R and R1different and then R is trihaloacetic and R1represents acetyl, or R represents triethyl or trimethylsilyl and R1represents acetyl

3. The method according to claim 2, where R and R1are trichloracetic.

4. The method according to claim 3, where the stage of protection of the hydroxyl in positions 7 and 10 is carried out with the help of trichloroacetaldehyde in methylene chloride in the presence of triethylamine and catalytic amounts of N,N-dimethylaminopyridine.

5. The method according to claims 1 to 4, where the oxidation of the hydroxyl in position 13 and hydroxylation in position 14 carry dioxide, magnesium dioxide or bismuth in a solvent selected from acetonitrile, mixtures of acetone or ethyl acetate/methylene chloride.

6. The method according to claims 1 to 5, where stage carboxylation of hydroxyl in positions 1 and 14 are carried out with phosgene in a mixture of methylene chloride/toluene in the presence of pyridine.

7. The method according to claims 1 to 6, where the stage of restoration to 13-hydroxy is carried out using sodium borohydride in methanol.

8. Intermediate reaction products:

13 dehydro-14β-hydroxy-10-deacetylbaccatin III

1,14-carbonate-13-degidro-7-triethylcitrate III

13 dehydro-14β-hydroxy-7,10-bestreplicawatches III

1,14-carbonate.



 

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< / BR>
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< / BR>
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< / BR>
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