HK1114838A - Process for the preparation of baccatin iii derivatives - Google Patents

Description

Process for preparing baccatin III derivatives

The application is a divisional application of Chinese patent application with the application number of 200510087313.6 and the invention name of 'a preparation method of baccatin III derivatives' filed on 28.7.2005, which is a divisional application of international application with the application number of PCT/EP01/08730 and the invention name of 'a preparation method of baccatin III derivatives' filed on 27.7.2001, and the international application enters the Chinese national stage on 8.2.8.2003 and the application number of 01813867.5.

The present invention relates to novel intermediates useful in the synthesis of 14 beta-hydroxy-1, 14-carbonate-deacetylbaccatin III derivatives and to processes for their preparation. The intermediate obtained by the method can be used for preparing novel taxane derivatives with antitumor activity.

Taxanes are the most important class of antineoplastic agents developed in recent years. Paclitaxel, a complex diterpene, is isolated from the bark of Taxus brevifolia (Taxus brevifolia), and is considered a "lead compound" for cancer therapy. At present, extensive research is being conducted on taxane derivatives having higher pharmacological activities and improved pharmacokinetic properties. Particular research relates to baccatin III derivatives with various modifications to the basic structure. Examples of such compounds are the 14 β -hydroxybaccatin III derivatives disclosed in the following documents: US5,705,508, WO 97/43291, WO 96/36622. At present, 14 β -hydroxy-1, 14-carbonate-deacetylbaccatin III derivatives are prepared starting from 14 β -hydroxy-deacetylbaccatin III precursors, which are natural compounds and can be extracted in small amounts from the leaves of taxus cuspidata (Taxuswallichiana), as described in EP 559,019. At present, there is a strong need for new derivatives and alternatives to those commonly used methods by which 14 β -hydroxy-1, 14-carbonate-deacetylbaccatin III derivatives can be prepared simply and efficiently.

It has been found that 14 β -hydroxy-1, 14-carbonate-deacetylbaccatin III can be prepared using 10-deacetylbaccatin III as a starting compound, and that, unlike 14 β -hydroxy-baccatin III, such 10-deacetylbaccatin III can be isolated in large quantities from the leaves of Taxus baccata (Taxusbaccata).

Accordingly, the present invention provides a process for the preparation of 14 β -hydroxy-1, 14-carbonate-deacetylbaccatin III comprising the steps of:

1. protection of the hydroxyl groups at the 7-and 10-positions of 10-deacetylbaccatin III:

wherein R and R₁Selected from hydrogen, C₁-C₁₀Alkyl or aryl, C₁-C₁₀Alkyl-or aryl-carbonyl, trichloroacetyl, C₁-C₄A trialkylsilyl group; preferably, when R and R are₁When the same are the same, they are each trichloroacetyl group, and when they are different, preferably R is trichloroacetyl group and R is₁Is acetyl, or R is triethyl-or trimethyl-silyl and R is₁Is acetyl;

2. the two-step oxidation gives the derivatives oxidized at the 13-position and hydroxylated at the 14-position:

3. carbonating the adjacent hydroxyl groups at the 1-position and the 14-position to obtain a 1, 14-carbonate derivative:

4. reduction of the carbonyl group at the 13-position:

5. removing the protecting groups at the 7-and 10-positions:

methods for protecting the 7-and 10-hydroxyl groups are described in the following documents: holton et al Tetrahedron Letters 39, (1998) 2883-. Due to the different reactivity, it is possible to selectively protect the hydroxyl groups of the starting compound deacetylbaccatin III. Specifically, the reactivity towards the acylating, alkylating or silylating agent varies in the following order: c (7) -OH > C (10) -OH > C (13) -OH > C (1) -OH, and thus the groups at the 7-and 10-positions can be selectively protected while leaving the hydroxyl groups at the 1-and 13-positions free.

Furthermore, by changing the reaction conditions, the order of reactivity of the hydroxyl groups at the 7-and 10-positions can be reversed, so that they can be differently substituted. Examples of reagents and reaction conditions for protecting the 10-and 7-hydroxyl groups are described in the publications cited above.

The oxidation step of the hydroxyl group at the 13-position may be carried out with manganese dioxide or bismuth dioxide, preferably manganese dioxide in acetonitrile or acetone, in a solvent selected from acetonitrile, acetone or an ethyl acetate/dichloromethane 9: 1 mixture, under vigorous stirring. The reaction proceeds very quickly to give the derivative oxidized at the 13-position, which can be recovered from the reaction medium, while a longer reaction will give the derivative oxidized at the 13-position and hydroxylated at the 14-position.

The subsequent carbonation step on the hydroxyl groups in the 1-and 14-positions is generally carried out with phosgene or triphosgene in a dichloromethane/toluene mixture in the presence of pyridine. The 1, 14-carbonate derivative formed is then readily reduced at the 13-position to give the corresponding 13-hydroxy derivative. The reduction reaction proceeds regioselectively at the carbonyl group in the 13-position, while the carbonyl group in the 9-position remains unchanged and the 13-alpha isomer is obtained stereoselectively almost exclusively. The reaction can generally be carried out with sodium borohydride in methanol in high yield. The last step is to carry out deprotection on the hydroxyl groups at the 7-position and the 10-position to obtain the final product 14 beta-hydroxyl-1, 14-carbonic ester deacetylation baccatin III. The conditions and reagents used for selective deprotection of the hydroxyl groups at the 7-and 10-positions are described in the following references: zheng et al, Tetrahedron lett, 1995, 36, 2001, and Datta et al, j. The resulting end products are extremely useful intermediates in the synthesis of various taxane derivatives. As mentioned previously, said intermediates have so far been prepared in low yields using 14 β -hydroxybaccatin III extracted from Taxus cuspidata leaves. The process of the invention allows the preparation of the same intermediates in high yields, the starting materials used being available in large quantities. Examples of compounds with antitumor activity prepared starting from 14 β -hydroxy-1, 14-carbonate deacetylbaccatin III are described in the following documents: US5,705,508, WO 97/43291, WO 96/36622.

According to a preferred embodiment of the invention, deacetylbaccatin III is reacted with trichloroacetyl chloride in dichloromethane in the presence of triethylamine using catalytic amounts of N, N-Dimethylaminopyridine (DMAP). The use of trichloroacetic acid esters as protecting groups has proven to be very advantageous in the oxidation, carbonation and reduction steps of the process according to the invention. In particular, the oxidized and carbonated 7, 10-bistrichloroacetate derivative (obtained in quantitative yield from the starting compound) can be easily reduced at the 13-position and the trichloroacetate group removed simultaneously, giving 14 β -hydroxy-1, 14-carbonate-deacetylbaccatin III. The use of catalytic amounts of DMAP offers clear advantages from an industrial and environmental point of view, since the acylation of this substance has so far been carried out in pyridine, with the problem of residual solvent emissions.

The following intermediates obtained according to the preferred embodiment described above also form part of the present invention:

the following examples illustrate the invention in more detail.

Example I

Preparation of 7, 10-bistrichloroacetyl-10-deacetylbaccatin III

The first method comprises the following steps:

4.77ml of trichloroacetic anhydride (42.32mmol) are added dropwise to a solution of 10g of 10-deacetylbaccatin III (18.4mmol) in 125ml of anhydrous dichloromethane and 42ml of pyridine. The reaction mixture was stirred for 3 hours or until the reaction was complete, checked by silica gel TLC using n-hexane/ethyl acetate 1: 1 mixture as eluent. After completion of the reaction, 5ml of methanol was added to destroy excess trichloroacetic anhydride, and then water was added. The organic phase was washed thoroughly with acidic water (HCl) to remove pyridine, then the remaining organic phase was dried over magnesium sulfate, concentrated to dryness in vacuo to give a pale yellow solid (17g), which was crystallized from chloroform: [ alpha ] to]_D-34 (dichloromethane C5.8); IR (KBr)3517, 1771, 1728, 1240, 981, 819, 787, 675cm^-1；

¹H-NMR (200 MHz): δ 8.11(Bz C), 7.46(Bz, BB'), 6.50(s, H-10), 5.72(m, H-7H-29), 5.02(d, J ═ 8Hz, H-5), 4.95(m, H-13), 4.37(d, J ═ 8Hz, H-20a), 4.18(d, J ═ 8Hz, H-20b), 4.02(d, J ═ 6Hz, H-3), 2.32(s, 4-Ac), 2.22(s, H-18), 1.91(s, H-19), 1.25 and 1.11(s, H-16, H-17), 1.94(m, H14 α), 1.89(m, H14 β).

The second method comprises the following steps:

10-deacetylbaccatin III (10g, 18.38mmol) was suspended in dichloromethane (120ml), DMAP (220mg, 1.4mmol, 0.1 equiv.) was added and cooled to 0 ℃ in an ice bath. Triethylamine (10.26ml, 73.6mmol, 4 equiv.) was added followed immediately by Cl addition under a nitrogen stream over 5 minutes₃CCOCl (4.12ml, 36.8mmol, 2 equiv.) was maintained at a temperature below 10 ℃. After the addition was complete, the mixture was stirred in an ice bath for 15 minutes, then the ice bath was removed and stirred at room temperature for 1 hour. After 1 hour, the reaction was checked by TLC (ethyl acetate 2/n-hexane 3, Rf 10-DAB III 0.05, Rf7, 10-bistrichloroacetyl-10-DAB III 0.26) and Cl was added₃CCOCl (1ml, 0.5 equiv). Stirring was continued for 10 minutes at room temperature, then the reaction was poured into a beaker containing 160g of crushed ice and allowed to stand with stirring until equilibrium was reached at room temperature (about 1 hour). The aqueous phase was separated and extracted with dichloromethane (3X 40 ml). The combined organic phases were washed with 1N HCl (20ml) and then with NaHCO₃The saturated solution (20ml) was washed, dried over sodium sulfate and the solvent was distilled off. Crude product weight: 16.5 g. After crystallization in chloroform, IR,¹H-NMR and [ alpha ]]_DThe spectral values are identical to those obtained with pyridine and trichloroacetic anhydride.

Example II

Oxidation of 7, 10-Bitrichloroacetate 10-deacetylbaccatin III at the 13-position and Hydroxygenation at the 14-position Radication of

30g of activated MnO₂To a solution of 10-deacetylbaccatin III 7, 10-bistrichloroacetate (3g) in acetonitrile (40ml), the suspension was stirred at room temperature by means of a magnetic stirrer and the progress of the reaction was checked by TLC (petroleum ether-ethyl acetate 5: 5; Rf of starting material approx. 0.31). After about 1 hour, the formation of the 13-dehydro derivative was complete (TLC analysis, Rf of 13-dehydro derivative was about 0.50). Stirring was continued for about 72 hours during which time the 13-dehydro derivative was slowly oxidized to the corresponding 14 β -hydroxy derivative (Rf about 0.36). The reaction mixture was filtered through celite and the filter cake was reusedAnd washing with ethyl acetate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (100ml, eluent: petroleum ether-ethyl acetate 7: 3) to give 170mg of the 13-dehydro-derivative and 2.38g of the 14. beta. -hydroxy-13-dehydro-derivative.

13-dehydro-14 β -hydroxy-10-deacetylbaccatin III, 7, 10-bistrichloroacetate: white powder, m.p.97 ℃; IR (KBr sheet): 3440, 1780, 1767, 1736, 1686, 1267, 1232, 1103, 1010, 854cm^-1；¹H-NMR(200MHz，CDCl₃): δ 8.07(Bz AA '), 7.60(Bz, C), 7.49(Bz, BB'), 6.52(s, H-10), 5.92(d, J ═ 6.7Hz, H-2), 5.70(br t, J ═ 8.0Hz, H-7), 4.95(br d, J ═ 8.2Hz, H-5), 4.37(d, J ═ 8.2Hz, H-20a), 4.31(d, J ═ 8.2Hz, H-20b), 4.17(s, H14), 4.02(d, J ═ 6.7Hz, H-3), 2.71(m, H-6), 2.29(s, OAc), 2.17(s, OAc), 1.96(s, H-18), 1.27, 1.01(s, H-16, H-19, and H-19).

Example III

Oxidation/hydroxylation of 7-triethylsilylbaccatin III

10g of activated MnO₂To a solution of 7-triethylsilylbaccatin III (1.0g) in acetonitrile (10ml), the suspension was stirred at room temperature with a magnetic stirrer and the progress of the reaction was monitored by TLC (petroleum ether-ethyl acetate 6: 4; Rf of starting material was about 0.25). After about 2 hours, the formation of the 13-dehydro derivative was complete (TLC analysis, Rf of 13-dehydro derivative was about 0.45). Stirring was continued for 188 hours, during which time MnO was added₂(10g) In that respect The 13-dehydro derivative was slowly oxidized to the corresponding 14 β -hydroxy derivative (Rf about 0.38). The reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (40ml, eluent: petroleum ether-ethyl acetate 7: 3) to give 126mg of a 13-dehydro-derivative, 479mg (46%) of a 14 β -hydroxy-13-dehydro-derivative and 189mg of a mixture of the two.

13-dehydro-7-triethylsilylbaccatin III, white powder, m.p.168℃。[α]_D ²⁵-35 (dichloromethane, C0.67); IR (KBr)3488, 1726, 1711, 1676, 1373, 1269, 1244, 1230, 1105cm^-1；¹H-NMR(200MHz，CDCl₃): δ 8.07(Bz AA '), 7.60(Bz, C), 7.49(Bz, BB'), 6.59(s, H-10), 5.69(d, J ═ 6.9Hz, H-2), 4.92(d, J ═ 8.2Hz, H-5), 4.48(dd, J ═ 10.6Hz, H-7), 4.33(d, J ═ 8.0Hz, H-20a), 4.12(d, J ═ 8.0Hz, H-20b), 3.91, (d, J ═ 6.9Hz, H-3), 2.96(d, J ═ 20Hz, H-14a), 2.65(d, J ═ 20Hz, H-20b), 2.50(m, H-6 α), 2.23(s, OAc), 2.19(s, 18H-1, 19H-19, H-19, 1.19, H-19, and TES (16, H-17).

13-dehydro-14 β -hydroxy-10-deacetylbaccatin III, 7, 10-bistrichloroacetate: white powder, m.p.153 ℃; [ alpha ] to]_D ²⁵+20 (dichloromethane, C0.75); IR (KBr)3431, 1723, 1692, 1371, 1269, 1242, 1223, 1096cm^-1；¹H-NMR(500MHz，CDCl₃): δ 8.06(Bz AA '), 7.60(Bz, C), 7.48(Bz, BB'), 6.51(s, H-10), 5.88(d, J ═ 6.9Hz, H-2), 4.90(d, J ═ 8.2Hz, H-5), 4.47(dd, J ═ 10.67Hz, H-7), 4.30(d, J ═ 8Hz, H-20a), 4.28(d, J ═ 8.2Hz, H-20b), 4.13(br d, J ═ 2Hz, H-14), 3.84(d, J ═ 6.9Hz, H-3), 3.69(br d, J ═ 2Hz, 14-OH), 3.62(s, 1-OH), 2.52(m, H-6 α), 2.24(s, 2.92, 2.21, 2, C), 2.18, 17-H-1, 17, 16, 17, 16, 17, 16, 0.94(m, TES), 0.59(m, TES). HRNS: 714.3092 (C)₃₇H₅₀O₁₂Calculated Si 714.3092).

Example IV

Oxidation/hydroxylation of 7-triethylsilylbaccatin III

10g of activated MnO₂Added to a solution of 7-triethylsilylbaccatin III (1.0g) in acetonitrile (10ml), the suspension was stirred at room temperature with a magnetic stirrer and the progress of the reaction was monitored by TLC (petroleum ether-ethyl acetate 6: 4; Rf of the starting material was approximately0.25). After about 2 hours, the formation of the 13-dehydro derivative was complete (TLC analysis, Rf of 13-dehydro derivative was about 0.45). Stirring was continued for 188 hours, during which time MnO was added₂(10g) In that respect The 13-dehydro derivative was slowly oxidized to the corresponding 14 β -hydroxy derivative (Rf about 0.38). The reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (40ml, eluent: petroleum ether-ethyl acetate 7: 3) to give 126mg of a 13-dehydro-derivative, 479mg (46%) of a 14 β -hydroxy-13-dehydro-derivative and 189mg of a mixture of the two.

13-dehydro-7-triethylsilylbaccatin III. White powder, m.p.210 ℃; [ alpha ] to]_D ²⁵-48 (dichloromethane, C0.50); IR (KBr)3478, 1728, 1676, 1373, 1271, 1240, 1071, 1026cm^-1；¹H-NMR(200MHz，CDCl₃): δ 8.07(Bz AA '), 7.64(Bz, C), 7.50(Bz, BB'), 6.46(s, H-10), 5.70(d, J ═ 6.9Hz, H-2), 4.95(d, J ═ 8.2Hz, H-5), 4.51(dd, J ═ 10.7Hz, H-7), 4.32(d, J ═ 8.4Hz, H-20a), 4.14(d, J ═ 8.4Hz, H-20b), 3.92, (d, J ═ 6.9Hz, H-3), 2.99(d, J ═ 20Hz, H-14a), 2.68(d, J ═ 20Hz, H-14b), 2.56(m, H-6 α), 2.29(s, OAc), 2.18(s, C), 2.68(d, J ═ 20Hz, H-14b), 2.56(m, H-6 α), 2.29(s, OAc), 2.18(s, 2.18, C), 1.19H-17H-1, and 17H-1.

13-dehydro-14 β -hydroxy-7-triethylsilylbaccatin III: white powder, m.p.220 ℃; [ alpha ] to]_D ²⁵+19 (dichloromethane, C0.42); IR (KBr)3568, 1710, 1719, 1686, 1372, 1282, 1240, 1219, 1073cm^-1；¹H-NMR(200MHz，CDCl₃): δ 8.09(BzAA '), 7.60(Bz, C), 7.51(Bz, BB'), 6.39(s, H-10), 5.89(d, J ═ 6.9Hz, H-2), 4.94(d, J ═ 8.2Hz, H-5), 4.47(dd, J ═ 10.7Hz, H-7), 4.31(br s, -H-20a + H-20b), 4.15(s, H-14), 3.69(d, J ═ 6.9Hz, H-3), 2.29(s, OAc), 2.16(s, H-18), 2.14(s, OAc), 1.74, 1.21, 1.10(s, H-16, H-17, and H-19), HRMS: 600.61120.19 (C)₃₁H₃₆O₁₂Calculated Si 600.6103).

Example V

Preparation of 1, 14-carbonate-13-dehydro-7-triethylsilyl-baccatin III

A solution of 13-dehydro-14 β -hydroxy-7-triethylsilylbaccatin III (124mg, 1.17mMol) in dichloromethane (1ml) and pyridine (0.56ml, 6.8mMol, 20 molar equivalents) was added dropwise over 5 minutes to a solution of phosgene (1.8ml of a 20% solution in toluene, 3.4mMol, 20 molar equivalents) in dichloromethane (2 ml). The mixture was stirred at room temperature for 1 hour, followed by neutralization of excess phosgene with a saturated solution of sodium bicarbonate and extraction with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate. The solvent was distilled off to leave a red residue which was purified over a small silica gel column (ca. 5ml, eluent: hexane/ethyl acetate 8: 2) to give 118mg (92%) of carbonate. When the reaction was carried out using triethylamine as a base without reverse addition, a mixture (about 1: 15) of 1, 14-carbonate and 2-debenzoyl-1, 2-carbonate-14-benzoate was obtained.

13-dehydro-14 β -hydroxy-7-triethylsilylbaccatin III1, 14-carbonate, white powder, m.p.153 ℃; [ alpha ] to]_D ²⁵+23 (dichloromethane, C0.75) ir (kbr); bands OH numbers 1834, 1734, 1709, 1373, 1242, 1225, 1088, 1057cm^-1；¹H-NMR(200MHz，CDCl₃): δ 7.99(Bz AA '), 7.60(Bz, C), 7.48(Bz, BB'), 6.51(s, H-10), 6.12(d, J ═ 6.9Hz, H-2), 4.90(d, J ═ 8.2Hz, H-5), 4.78(s, H-14), 4.44(dd, J ═ 10.7Hz, H-7), 4.34(d, J ═ 8Hz, H-20a), 4.19(d, J ═ 8.2Hz, H-20b), 3.80(d, J ═ 6.9Hz, H-3), 2.50(m, H-6 α), 2.23(s, OAc), 2.22(s, OAc), 2.19(s, H-18), 1.92(m, H-6 β), 1.72 (m), 1.72 (s, 1.39, H-19 (s, TES), 17-0.17 (m), TES, H-20 (m). HRNS: 740.2851 (C)₃₈H₄₈O₁₃Calculated Si 740.2864).

13-dehydro-14 beta-hydroxybaccatin III1, 14-carbonAcid esters, white powders; 240 ℃; [ alpha ] to]_D ²⁵-2.5 (dichloromethane, C0.4); IR (KBr)3539, 1831, 1736, 1240, 1088, 1068, 1057, 1024cm^-1；¹H-NMR(200MHz，CDCl₃): δ 7.98(Bz AA '), 7.61(Bz, C), 7.50(Bz, BB'), 6.39(s, H-10), 6.14(d, J ═ 6.9Hz, H-2), 4.98(d, J ═ 8.2Hz, H-5), 4.80(s, H-14), 4.43(dd, J ═ 10.7Hz, H-7), 4.35(d, J ═ 8Hz, H-20a), 4.24(d, J ═ 8.2Hz, H-20b), 3.80(d, J ═ 6.9Hz, H-3), 2.50(m, H-6 α), 2.30(s, OAc), 2.20(s, OAc), 2.15(s, H-18), 1.90(m, H-6 β), 1.74, 1.34, H-19, H-17, hrh-17: 626.2005 (C)₃₃H₃₄O₁Calculated value 626.1999).

Example VI

Preparation of 1, 14-carbonate-7-O-triethylsilylbaccatin III

Adding excess NaBH₄(about 20mg) was added in small portions to a solution of 13-dehydro-14 β -hydroxy-7-triethylsilylbaccatin III1, 14-carbonate (50mg) in methanol (5 ml). After 30 minutes, saturated ammonium chloride was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and the solvent was removed to give a residue, which was purified by silica gel column chromatography (about 5ml, eluting with hexane-ethyl acetate 8: 2) to give 35mg of the 13 α -hydroxy derivative and 9mg of the 13 β -hydroxy derivative.

14 β -hydroxy-7-triethylsilylbaccatin III1, 14-carbonate; [ alpha ] to]_D ²⁵-35 (dichloromethane, C0.60); IR (KBr)3054, 1819, 1736, 1603, 1371, 1261, 1238, 1090, 1069, cm^-1；¹H-NMR(200MHz，CDCl₃)：δ8.06(Bz AA′)，7.65(Bz，C)，7.50(Bz，BB′)，6.47(s，H-10)，6.12(d，J＝6.9Hz，H-2)，5.05(br d，J＝5.5Hz，H-13)，4.98(br d，J＝9Hz，H-5)，4.83(d，J＝5Hz，H-14)，4.50(dd，J＝10.7Hz，H-7)，4.34(d，J＝8Hz，H-20a)，4.23(d，J＝8Hz，H-20b)，3.75(d，J＝6.9Hz，H-3) 2.56(m, H-6 α), 2.34(s, OAc), 2.22(s, OAc), 1.78(m, H-6 β), 1.35(s, H-18), 1.75, 1.18, 0.95(s, -H-16, H-17 and H-19), 0.90(m, TES), 0.62(m, TES).

14 β -hydroxy-7-triethylsilyl-13-epibaccatin (epibaccatin) III1, 14-carbonate, amorphous; [ alpha ] to]_D ²⁵-13 (dichloromethane, C0.60); IR (KBr)3630, 1825, 1734, 1603, 1375, 1262, 1091, 1071, 1049cm^-1；¹H-NMR(200MHz，CDCl₃): δ 8.01(Bz AA '), 7.63(Bz, C), 7.48(Bz, BB'), 6.44(s, H-10), 6.12(d, J ═ 7.2Hz, H-2), 4.90(br d, J ═ 9Hz, H-5), 4.81(d, J ═ 8Hz, H-14), 4.48(br, J ═ 8Hz, H-13), 4.50(dd, J ═ 10, 7Hz, H-7), 4.41(d, J ═ 8Hz, H-20a), 4.31(d, J ═ 8Hz, H-20b), 3.68(d, J ═ 7.2Hz, H-3), 2.60(m, H-6 α), 2.32(s, OAc), 2.26(s, H-18), 2.21(s, H-18), 1.80 (s, H-6 (s, 1.3), 1.17-7 (H-3), 1.61, H-3 (m, H-6 α), 2.32(s, OAc), 2.26(s, 17, H-3, 17, H-61, and TES (H-3), TES).

Example VII

Preparation of 13-dehydro-14 beta-hydroxy-7, 10-bistrichloroacetyl-baccatin III1, 14-carbonate

A solution of 13-dehydro-14 β -hydroxy-7, 10-bistrichloroacetylbaccatin III (200mg) in dichloromethane (2ml) and pyridine (1.12ml, 20 equivalents) was added to a solution of phosgene (20% in toluene, 3.6ml, 20 equivalents) in dichloromethane (2ml) over a period of 5 minutes. The mixture was stirred at room temperature for 1 hour, followed by neutralization of excess phosgene with a saturated solution of sodium bicarbonate (3 ml). The mixture was extracted with dichloromethane and the organic phase was washed with saturated sodium bicarbonate solution, then with saturated sodium chloride solution and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate 9: 1) to give 175mg (89%) of a carbonate ester.

13-dehydro-14 beta-hydroxy-7, 10-bistrichloroacetyl-baccatin III1, 14-carbonate, amorphous whiteA colored solid. IR (KBr)1834, 1771, 1735, 1709, 1232, 1103, 1010, 854cm^-1。

¹H NMR(200MHz，CDCl₃)：δ＝8.03(Bz AA′)，7.60(Bz，C)，7.50(Bz，BB′)，6.52(s，H-10)，5.92(d，J＝6.7Hz，H-2)，5.70(br t，J＝8.0Hz，H-7)，4.95(br d，J＝8.2Hz，H-20b)，4.77(s，H-14)，4.02(d，J＝6.7Hz，H-3)，2.71(m，H-6)，2.29(s，OAc)，1.96(s，H-18)，1.27-1.01(m，H-16，H-17，H-19)。

Example VIII

Preparation of 14 beta-hydroxy-10-deacetylbaccatin III1, 14-carbonate

A solution of 13-dehydro-14 β -hydroxy-7, 10-bistrichloroacetyl-baccatin III1, 14-carbonate (500mg) in methanol (8ml) was cooled to 0 ℃ in an ice bath and solid NaBH was added over 5 minutes₄(44 mg). The mixture was stirred at room temperature for 1 hour and then cooled to ℃. Acetone (2ml) was added over 5 minutes and the mixture was concentrated then ethyl acetate (10ml) was added and filtered through celite. The clear solution was washed with a saturated solution of sodium chloride and dried over sodium sulfate. The solvent was distilled off to leave a residue (4.5: 1 mixture of C13 epimers) which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate 1: 1) to give 251mg of the 13. beta. epimer and 55mg of the 13. alpha. epimer of the deprotected carbonate (total 88%).

13 α -14 β -hydroxy-10-deacetylbaccatin III1, 14-carbonate. Amorphous white solid. IR (KBr): 3520(OH), 1834, 1709, 1232, 1103, 1010, 854cm^-1。

¹H NMR(200MHz，CDCl₃)：δ＝8.03(Bz AA′)，7.60(Bz，C)，7.50(Bz，BB′)，6.27(s，H-10)，5.92(d，J＝6.7Hz，H-2)，4.95(br d，J＝8.2Hz，H-20b)，4.85(m，H-13)，4.77(s，H-14)，4.42(br t，J＝8.0Hz，H-7)，4.02(d，J＝6.7Hz，H-3)，2.71(m，H-6)，2.29(s，OAc)，1.96(s，H-18)，1.27-1.01(m，H-16，H-17，H-19)。

13 α -14 β -hydroxy-10-deacetylbaccatin III1, 14-carbonate, amorphous white solid. IR (KBr): 3520(OH), 1834, 1709, 1232, 1103, 1010, 854cm^-1。

¹H NMR(200MHz，CDCl₃)：δ＝8.03(Bz AA′)，7.60(Bz，C)，7.50(Bz，BB′)，6.27(s，H-10)，5.92(d，J＝6.7Hz，H-2)，4.95(br d，J＝8.2Hz，H-20b)，4.80(m，H-13)，4.77(s，H-14)，4.42(br t，J＝8.0Hz，H-7)，4.02(d，J＝6.7Hz，H-3)，2.71(m，H-6)，2.29(s，OAc)，1.96(s，H-18)，1.27-1.01(m，H-16，H-17，H-19)。

Claims (1)

1. The following reaction intermediates:

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