Indian Patents. 268238:"A PROCESS FOR THE PREPARATION OF THE 14BETA-HYDROXY-BACCATIN III-1,14-CARBONATE"

Title of Invention	"A PROCESS FOR THE PREPARATION OF THE 14BETA-HYDROXY-BACCATIN III-1,14-CARBONATE"
Abstract	A process for the preparation of 14ß-hydroxy-baccatin III-l, 14-carbonate useful for the preparation of novel taxane derivatives with antitumor activity.

Full Text	A PROCESS FOR THE PREPARATION OF THE 14BETA-HYDROXY-BACCATINIII-114-CARBONATE The present invention relates to a process for the preparation of 14(3-hydroxy-l,14-carbonate-baccatin III. The product obtained with the process of the invention can be used in the preparation of novel taxane derivatives with antitumor activity. Taxanes are one of the most important classes of antitumor agents developed in recent years. Paclitaxel is a diterpene complex obtained from the bark of Taxus brevifolia and is considered one of the major medicaments for the therapy of cancer. At present, an extensive search is being carried out for novel taxane derivatives having superior pharmacological activity and improved pharmacokinetic profile. A specific approach relates to baccatin III derivatives variously modified with respect to the parent structure. Examples of said compounds are represented by the 14(3-hydroxy baccatin III derivatives disclosed in US 5705508, WO 97/43291, WO 96/36622. At present, 14p-hydroxy-deacetylbaccatin III 1,14-carbonate derivatives are prepared starting from the precursor 14P-hydroxy-deacetylbaccatin III, which is a natural compound obtainable in small amounts by extraction of the leaves of Taxus wallichiana, as disclosed in EP 559 019. There is strong need for novel processes for the easy, effective preparation of large amounts of 14\|3-hydroxy-l,14-carbonate-baccatin III, and hence the derivatives thereof. It has now been found that 14ß-hydroxy -baccatin III-1,14-carbonate can be prepared with a process starting from 13-ketobaccatin III, which compound can be easily obtained from 10-deacetylbaccatin III, which can in turn be easily isolated in large amounts from the leaves of Taxus baccata, contrary to 14ß-hydroxy-baccatin III. Therefore, the invention relates to a process for the preparation of 140-hydroxy-baccatin III-l,14-carbonate which comprises the following steps: a. treatment of 7-triethylsilyl-13-ketobaccatin III of formula (Formula Removed)with suitable bases and oxidizing agents, to give 7-triethylsilyl-13-keto-14-hydroxy-baccatin III: (Formula Removed)b. carbonation of the 1 and 14 hydroxyls to give 14p-Hydroxy-7- triethylsilyl -13-keto-baccatin III-l,14-carbonate: (Formula Removed)c. reduction of the ketone at the 13- position and cleavage of the protecting group in 7. Starting 13-ketobaccatin III is conveniently protected at the 7- position with a suitable protective group, preferably selected from silyl ethers (preferably triethylsilyl ether). Step a) is carried out by treatment with a suitable base, in particular potassium t-butoxide (t-BuOK) or potassium bis(trimethylsilyl)amide (KHMDS). The reaction can be carried out at -40 to -78°C. Suitable solvents for this reaction are ethers, such as tetrahydrofuran or diethyl ether, in particular in mixture with hexamethylphosphoramide (HMPA) or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone (DMPU). The enolate is then treated with an oxidizing agent, such as oxaziridine derivatives (in particular N-benzenesulfonyl phenyl oxaziridine, N-benzenesulfonyl in-nitrophenyl oxaziridine and camphorsulfonyloxaziridine) to provide the 7-protected 13-keto-14-hydroxy-baccatin III derivative. Step b) is then carried out by treatment with a carbonylating agent (for example carbonyldiimidazole or phosgene) under the conditions usually described in literature, to provide the 1,14-carbonate derivative. The reaction can be conveniently carried out in inert solvents, preferably ethers or chlorinated solvents, in the presence of a base (preferably pyridine or triethylamine), at a temperature ranging from -40°C to room temperature. The reaction can be carried out both on the pure starting material and on the crude from the previous step. The reduction of the carbonyl at the 13- position of step c) is easily carried out with sodium borohydride in ethanol at a temperature usually ranging from -20 to -50°C, and is completed within 2-6 hours. The reaction can also be carried out in methanol, isopropanol, or in a methanol and tetrahydrofuran mixture. The reducing agent can be used in stoichiometric amount, although an excess of hydride is preferably used. The reduction can also be effected with other hydrides, preferably tetrabutylammonium borohydride, lithium borohydride, sodium triacetoxy borohydride, in the conditions known in the art. Protection at the 7- position is removed under conditions depending on the protective group used. For example, if the protective group at the 7-position is triethylsilyl ether, hydrolysis with hydrochloric acid in methanol or hydrofluoric acid and pyridine in acetonitrile can successfully be used. 13-Keto-baccatin III can conveniently be prepared by oxidation of baccatin III. Oxidation of baccatin III can be carried out with ozone, or with manganese dioxide in aprotic solvents such as methylene chloride, tetrahydrofuran, acetone, ethyl acetate. The reaction can be carried out at '0°C - 60°C, more preferably at room temperature. The processes of the invention are summarized in the following scheme: (Scheme Removed)The following example further illustrates the invention. The abbreviations used are as follows: AcOEt = ethyl acetate; TES = triethylsilyl; TESCI = triethylsilyl chloride; DCM = dichloromethane, THF = tetrahydrofuran. EXAMPLE a) 13-Keto-baccatinIII Baccatin III (150 g, 0.25 mol) was dissolved in acetone (1.43 L). Commercially available manganese dioxide (450 g) was added in three portions under strong stirring. After the starting product disappeared (4 h) the suspension was filtered and the solvent evaporated off. The crude was suspended in AcOEt (100 ml) and re fluxed for 1 h, then c-Hexane (100 ml) was added. The title compound was obtained from mother liquors, after evaporation of the solvent, as a white solid (140 g, 95%). b) 7-TES-13-keto-baccatin III 13-Keto-baccatin III (5 g, 8.5 mmol), TESC1 (3.6mL, 21.4 mmol, 2.5 eq) and N-methylimidazole (2.73 mL, 34.3 mmol, 4 eq) were dissolved in anhydrous DCM (25 ml). The solution was left under stirring for 1.5h then quenched by slowly pouring it into 2M NaHSO4 (25 ml). The aqueous layer was washed, extracted with DCM (2 x 10 ml) and the combined organic layers were extracted with brine (2 x 20 ml). The organic solution was dried over sodium sulfate to give 4.7 g of the title compound, sufficiently pure for the subsequent step. M.p.: 212°C. TLC: cHex-AcOEt 1:1, Rf=0.57. 1H-NMR (200 MHz, CDC13) 8 0.58-0.66 (m, 6H, Si-CH2); 0.90-0.98 (t, 7=8.4, 9H, CH2CH3y, 1.21 (s, 3H, 17-Me); 1.27 (s, 3H, 16,-Me); 1.69 (s, 3H, 19-Me); 1.83-1.96 (m, 1H, 6-H); 2.20 (s, 3H, 18-Me); 2.21 (s, 3H, 10-OAc); 2.25 (s, 3H, 4-OAc); 2.48-2.65 (m, 1H, 6-H); 2.81 (ABq, 2H, 14-H); 3.93 (d, J=6.6, 1H, 3-H); 4.25 (ABq, 2H, 20-H); 4.51 (dd, J=10,6, 7.0, 1H, 7-H); 4.94 (d, J=l.l, 1H, 5-H); 5.72 (d, 7= 7.0, 1H, 2-H); 6.61 (s, 1H, 10-H); 7.52 (t, 7=6.2, 2H, Bz); 7.64 (t, J=6.2, 1H, Bz); 8.10 (dd, 7=7.4, 1.1, 2H, Bz). c) 14-Hvdroxv-7-TES-13-keto-baccatin III 7-TES-13-keto-baccatin III (670 mg, 0.96 mmol) was dissolved in a mixture of anhydrous THF (9 ml) and DMPU (2 ml) and cooled to -60°C under N2. A 1M solution of f-BuOK in THF (2.5 ml, 0.86 mmol), previously cooled to -50°C, was dropped therein. This solution was stirred at -60°C for 45 minutes, then added drop by drop with (±)-camphorsulfonyl-oxaziridine (440 mg, 2 mmol) dissolved in anhydrous THF (2 ml). The reaction mixture was stirred for 3 hours at -60°C then quenched with a 10% AcOH solution in anhydrous THF (2 ml). The mixture was then left to warm at room temperature, then extracted with DCM (2 x 10 ml). The combined organic layers were washed with water, a NaCl saturated aqueous solution of (15 ml) and dried over Na2SO4. The title compound was purified by flash chromatography (silica gel, cHex- AcOEt, 8:2) in a 79% yield. Alternatively, this was used directly in the subsequent step without further purification. M.p.: 94-98°C. TLC: cHex-AcOEt 1:1, Rf=0.5. 'H-NMR (200 MHz, CDC13) 5 0.58-0.66 (m, 6H, Si-CH2); 0.91-0.99 (t, .7=8.7, 9H, CH2CH3); 1.24 (s, 3H, 17-Me); 1.28 (s, 3H, 16,-Me); 1.75 (s, 3H, 19-Me); 1.83-2.05 (m, IH, 6-H); 2.14 (s, 3H, 18-Me); 2.24 (s, 3H, 10-OAc); 2.26 (s, 3H, 4-OAc); 2.46-2.61 (m, IH, 6-H); 3.64 (s, IH, 1-OH) 3.73 (d, 7=1.8, IH, 14-OH); 3.87 (d, J=6.9, IH, 3-H); 4.14 (d, 7=1.8, IH, 14-H); 4.31 (s, 2H, 20-H); 4.49 (dd, 7=10.7, 6.6, IH, 7-H); 4.93 (d, 7=7.3, IH, 5-H); 5.89 (d, J= 7.0, 1H, 2-H); 6.53 (s, 1H, 10-H); 7.46-7.66 (m, 3H, Bz); 8.08 (dd, 7=7.0, 1.5.2H, Bz) d) 14p-Hvdroxv-7-TES-13-keto-baccatinIII 1.14-carbonate A solution of 14f}-hydroxy-7-TES-13-keto-baccatin (12.2 g) in anhydrous DCM (50 ml) and pyridine (16 ml) was dropped in a 20% phosgene solution in DCM (45 mL, 5 eq) at -10°C. After 2 hours the reaction was added drop by drop with a 5% NaHC03 aqueous solution (100 ml). The aqueous layer was washed with DCM (3 x 50 ml) and the crude was purified by flash chromatography (silica gel, DCM-AcOEt=50:l) to give the title compound in a 95% yield. M.p.: 97-99°C. TLC: cHex-AcOEt 1:1, Rf=0.64. 'H-NMR (200 MHz, CDC13) 8 0.58-0.66 (m, 6H, Si-CH2); 0.91-0.99 (t, 7=8.7, 9H, CH2CH3); 1.21 (s, 3H, 17-Me); 1.39 (s, 3H, 16,-Me); 1.75 (s, 3H, 19-Me); 1.86-2.13 (m, 1H, 6-H); 2.22 (s, 3H, 18-Me); 2.25 (s, 3H, 10-OAc); 2.26 (s, 3H, 4-OAc); 2.48-2.63 (m, 1H, 6-H); 3.83 (d, 7=7.0, 1H, 3-H); 4.30 (ABq, 2H, 20-H); 4.49 (dd, 7=11.0, 7.0, IH, 7-H); 4.81 (s, 1H, 14-H); 4.93 (d, 7=7.3, 1H, 5-H); 6.15 (d, 7= 7.0, 1H, 2-H); 6.54 (s, IH, 10-H); 7.51 (t, 2H, Bz); 7.62-7.70 (m, IH, Bz); 8.01 (dd, 7-7.0, 1.9, 2H, Bz). e) 14ß-Hvdroxv-7-TES-baccatinIII 1.14-carbonate A suspension of NaBH4 (0.5 g) in absolute ethanol (10 ml) was cooled to -50°C, and added with a cooled solution of 14-hydroxy-7-TES-13-keto-baccatin III 1,14-p-carbonate (0.5 g, 0.6 mmol) in absolute ethanol (10 ml). After the starting product disappeared (8 h), the reaction was quenched with citric acid and extracted with AcOEt. The combined organic layers were dried over sodium sulfate and the solvent was evaporated off. The title compound was obtained as a white solid in an 85% yield, after chromatography. M.p.: 134-137°C. TLC: cHex-AcOEt 1:1, Rf=0.46. !H-NMR (200 MHz, CDC13) 6 0.58-0.66 (m, 6H, Si-CH2); 0.91-0.99 (t, .7=8.7, 9H, CH2CH3); 1.16 (s, 3H, 17-Me); 1.28 (s, 3H, 16,-Me); 1.74 (s, 3H, 19-Me); 1.85-2.14 (m, IH, 6-H); 2.06 (s, 3H, 18-Me); 2.21 (s, 3H, 10-OAc); 2.33 (s, 3H, 4-OAc); 2.47-2.65 (m, IH, 6-H); 3.74 (d, .7=7.4, IH, 3-H); 4.12-4.35 (m, 2H, 20-H); 4.49 (dd, .7=10.3, 6.6, IH, 7-H); 4.82 (d, IH, 14-H); 4.99 (d, J=7.3, IH, 5-H); 5.00-5.03 (m, IH, 13-H); 6.11 (d, J= 7.4, IH, 2-H); 6.45 (s, IH, 10-H); 7.50 (t, 2H, Bz); 7.60-7.68 (m, IH, Bz); 8.04 (dd, .7=7.0, 1.5, 2H, Bz). f) 14ß-Hydroxv-baccatinIII 1.14-carbonate 14-Hydroxy-7-TES-baccatin III 1,14-p-carbonate (9.6 g, 1.3 mmol) was dissolved in a mixture of acetonitrile (5.4 ml) and pyridine (6.4 ml) cooled to 0°C. A solution of 70% HF in pyridine (0.95 ml) was dropped in 15 min and the solution was stirred at room temperature overnight. The reaction mixture was then poured into 20 mL of ice and left under stirring for 1 h, then extracted with DCM (3 x 10 ml) and the combined organic layers were washed with 10% NaHSO4 (to pH=2), 5% NaHC03 (2x10 ml) and brine (2x10 ml). After evaporation of the solvent, the title compound was obtained as a white solid in a 96% yield. CLAIMS 1. A process for the preparation of 14p-hydroxy-l,14-carbonate-baccatin III, which comprises: a. treatment of 7-triethylsilyl-13-ketobaccatin III of formula (Formula Removed) with suitable bases and oxidizing agents, to give 7-triethylsilyl-13-keto-14-hydroxy-baccatin III: (Formula Removed) b. carbonation of the 1 and 14 hydroxyls to give 14p-Hydroxy-7-TES-13-keto-baccatin III-l,14-carbonate: (Formula Removed)c. reduction of the ketone at the 13- position and cleavage of the protective group in 7. 2. A process as claimed in claim 1 wherein step a) is carried out by treatment with potassium t-butoxide or potassium bis(trimethylsilyl)amide at a temperature from -40 to -78°C in ethers in admixture with hexamethylphosphoramide (HMPA) or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone (DMPU), in the presence of oxaziridine derivatives. 3. A process as claimed in claim 2 wherein the oxaziridine derivative is selected from N-benzenesulfonyl phenyl oxaziridine, N-benzenesulfonyl m- nitrophenyl oxaziridine and camphorsulfonyloxaziridine. 4. A process as claimed in any one of claims 1 to 3, wherein step h) is carried out by treatment with a carbonyldiimidazole or phosgene in chlorinated solvents in the presence of a base at temperatures ranging from -40°C to room temperature. 5. A process as claimed in any one of claims 1 to 4, wherein step c) is carried out by treatment with a hydride at a temperature from -20 to -50°C. 6. A process as claimed in claim 5 wherein the hydride is selected from sodium borohydride, lithium borohydride, sodium triacetoxy borohydride and the reaction is carried out in ethanol, methanol, isopropanol, or in a methanol and tetrahydrofuran mixture. 7. A process as claimed in any one of claims 1 to 6 wherein 13-keto- baccatin III protected at the hydroxyl in 7 is prepared by selective acetylation of the hydroxyl 10 followed by oxidation of the hydroxyl 13 and protection of the hydroxyl 7. 8. A process as claimed in claim 7 wherein 13-keto-baccatin III is obtained by selective acetylation of deacetylbaccatin III in 10 with acetic anhydride followed by oxidation with manganese dioxide in aprotic solvents at 0°C - 60°C. 9. As a novel intermediate, the compound 7-triethylsilyl-13-keto-14- (Formula Removed) hydroxy-baccatin III, of formula 10. As a novel intermediate, the compound 14p-Hydroxy-7-TES-13-keto- baccatin 111-1,14-carbonate, of formula : (Formula Removed) 11. A process for the preparation of 14ß-hydroxy-l, 14-carbonate-baccatin III substantially as herein described with reference to the foregoing description and the accompanying example. 12. Novel intermediate, the compound 7-triethylsilyl-13-keto-14- hydroxy-baccatin III substantially as herein described with reference to the foregoing description and the accompanying example. 13. Novel intermediate, thecompound 14ß-Hydroxy -7-TES-13-keto-baccatin III substantially as herein described with reference to the foregoing description and the accompanying example.

Full Text

A PROCESS FOR THE PREPARATION OF THE 14BETA-HYDROXY-BACCATINIII-114-CARBONATE
The present invention relates to a process for the preparation of 14(3-hydroxy-l,14-carbonate-baccatin III. The product obtained with the process of the invention can be used in the preparation of novel taxane derivatives with antitumor activity.
Taxanes are one of the most important classes of antitumor agents developed in recent years. Paclitaxel is a diterpene complex obtained from the bark of Taxus brevifolia and is considered one of the major medicaments for the therapy of cancer. At present, an extensive search is being carried out for novel taxane derivatives having superior pharmacological activity and improved pharmacokinetic profile. A specific approach relates to baccatin III derivatives variously modified with respect to the parent structure. Examples of said compounds are represented by the 14(3-hydroxy baccatin III derivatives disclosed in US 5705508, WO 97/43291, WO 96/36622. At present, 14p-hydroxy-deacetylbaccatin III 1,14-carbonate derivatives are prepared starting from the precursor 14P-hydroxy-deacetylbaccatin III, which is a natural compound obtainable in small amounts by extraction of the leaves of Taxus wallichiana, as disclosed in EP 559 019. There is strong need for novel processes for the easy, effective preparation of large amounts of 14|3-hydroxy-l,14-carbonate-baccatin III, and hence the derivatives thereof.
It has now been found that 14ß-hydroxy -baccatin III-1,14-carbonate can be prepared with a process starting from 13-ketobaccatin III, which compound can be easily obtained from 10-deacetylbaccatin III, which can in turn be easily isolated in large amounts from the leaves of Taxus baccata, contrary to 14ß-hydroxy-baccatin III.

Therefore, the invention relates to a process for the preparation of 140-hydroxy-baccatin III-l,14-carbonate which comprises the following steps: a. treatment of 7-triethylsilyl-13-ketobaccatin III of formula
(Formula Removed)with suitable bases and oxidizing agents, to give 7-triethylsilyl-13-keto-14-hydroxy-baccatin III:

(Formula Removed)b. carbonation of the 1 and 14 hydroxyls to give 14p-Hydroxy-7-
triethylsilyl -13-keto-baccatin III-l,14-carbonate:
(Formula Removed)c. reduction of the ketone at the 13- position and cleavage of the protecting group in 7.
Starting 13-ketobaccatin III is conveniently protected at the 7- position with a suitable protective group, preferably selected from silyl ethers
(preferably triethylsilyl ether). Step a) is carried out by treatment with a suitable base, in particular potassium t-butoxide (t-BuOK) or potassium bis(trimethylsilyl)amide (KHMDS). The reaction can be carried out at -40 to -78°C. Suitable solvents for this reaction are ethers, such as tetrahydrofuran or diethyl ether, in particular in mixture with hexamethylphosphoramide (HMPA) or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone (DMPU). The enolate is then treated with an oxidizing agent, such as oxaziridine derivatives (in particular N-benzenesulfonyl phenyl oxaziridine, N-benzenesulfonyl in-nitrophenyl oxaziridine and camphorsulfonyloxaziridine) to provide the 7-protected 13-keto-14-hydroxy-baccatin III derivative.
Step b) is then carried out by treatment with a carbonylating agent (for example carbonyldiimidazole or phosgene) under the conditions usually described in literature, to provide the 1,14-carbonate derivative. The reaction can be conveniently carried out in inert solvents, preferably ethers or chlorinated solvents, in the presence of a base (preferably pyridine or triethylamine), at a temperature ranging from -40°C to room temperature. The reaction can be carried out both on the pure starting material and on the crude from the previous step.
The reduction of the carbonyl at the 13- position of step c) is easily carried out with sodium borohydride in ethanol at a temperature usually ranging from -20 to -50°C, and is completed within 2-6 hours. The reaction can also be carried out in methanol, isopropanol, or in a methanol and tetrahydrofuran mixture. The reducing agent can be used in stoichiometric amount, although an excess of hydride is preferably used. The reduction can also be effected with other hydrides, preferably tetrabutylammonium borohydride, lithium borohydride, sodium triacetoxy borohydride, in the conditions known in the art.
Protection at the 7- position is removed under conditions depending on
the protective group used. For example, if the protective group at the 7-position is triethylsilyl ether, hydrolysis with hydrochloric acid in methanol or hydrofluoric acid and pyridine in acetonitrile can successfully be used.
13-Keto-baccatin III can conveniently be prepared by oxidation of
baccatin III. Oxidation of baccatin III can be carried out with ozone, or with
manganese dioxide in aprotic solvents such as methylene chloride,
tetrahydrofuran, acetone, ethyl acetate. The reaction can be carried out at
'0°C - 60°C, more preferably at room temperature.
The processes of the invention are summarized in the following scheme:
(Scheme Removed)The following example further illustrates the invention.
The abbreviations used are as follows:
AcOEt = ethyl acetate; TES = triethylsilyl; TESCI = triethylsilyl chloride; DCM = dichloromethane, THF = tetrahydrofuran.
EXAMPLE
a) 13-Keto-baccatinIII
Baccatin III (150 g, 0.25 mol) was dissolved in acetone (1.43 L). Commercially available manganese dioxide (450 g) was added in three portions under strong stirring. After the starting product disappeared (4 h) the suspension was filtered and the solvent evaporated off. The crude was
suspended in AcOEt (100 ml) and re fluxed for 1 h, then c-Hexane (100 ml) was added. The title compound was obtained from mother liquors, after evaporation of the solvent, as a white solid (140 g, 95%).
b) 7-TES-13-keto-baccatin III
13-Keto-baccatin III (5 g, 8.5 mmol), TESC1 (3.6mL, 21.4 mmol, 2.5 eq) and N-methylimidazole (2.73 mL, 34.3 mmol, 4 eq) were dissolved in anhydrous DCM (25 ml). The solution was left under stirring for 1.5h then quenched by slowly pouring it into 2M NaHSO4 (25 ml). The aqueous layer was washed, extracted with DCM (2 x 10 ml) and the combined organic layers were extracted with brine (2 x 20 ml). The organic solution was dried over sodium sulfate to give 4.7 g of the title compound, sufficiently pure for the subsequent step. M.p.: 212°C. TLC: cHex-AcOEt 1:1, Rf=0.57. 1H-NMR (200 MHz, CDC13) 8 0.58-0.66 (m, 6H, Si-CH2); 0.90-0.98 (t, 7=8.4, 9H, CH2CH3y, 1.21 (s, 3H, 17-Me); 1.27 (s, 3H, 16,-Me); 1.69 (s, 3H, 19-Me); 1.83-1.96 (m, 1H, 6-H); 2.20 (s, 3H, 18-Me); 2.21 (s, 3H, 10-OAc); 2.25 (s, 3H, 4-OAc); 2.48-2.65 (m, 1H, 6-H); 2.81 (ABq, 2H, 14-H); 3.93 (d, J=6.6, 1H, 3-H); 4.25 (ABq, 2H, 20-H); 4.51 (dd, J=10,6, 7.0, 1H, 7-H); 4.94 (d, J=l.l, 1H, 5-H); 5.72 (d, 7= 7.0, 1H, 2-H); 6.61 (s, 1H, 10-H); 7.52 (t, 7=6.2, 2H, Bz); 7.64 (t, J=6.2, 1H, Bz); 8.10 (dd, 7=7.4, 1.1, 2H, Bz).
c) 14-Hvdroxv-7-TES-13-keto-baccatin III
7-TES-13-keto-baccatin III (670 mg, 0.96 mmol) was dissolved in a
mixture of anhydrous THF (9 ml) and DMPU (2 ml) and cooled to -60°C under N2. A 1M solution of f-BuOK in THF (2.5 ml, 0.86 mmol), previously cooled to -50°C, was dropped therein. This solution was stirred at -60°C for 45 minutes, then added drop by drop with (±)-camphorsulfonyl-oxaziridine (440 mg, 2 mmol) dissolved in anhydrous THF (2 ml). The reaction mixture was stirred for 3 hours at -60°C then quenched with a 10% AcOH solution in anhydrous THF (2 ml). The mixture was then left to warm at room
temperature, then extracted with DCM (2 x 10 ml). The combined organic layers were washed with water, a NaCl saturated aqueous solution of (15 ml) and dried over Na2SO4. The title compound was purified by flash chromatography (silica gel, cHex- AcOEt, 8:2) in a 79% yield. Alternatively, this was used directly in the subsequent step without further purification. M.p.: 94-98°C. TLC: cHex-AcOEt 1:1, Rf=0.5. 'H-NMR (200 MHz, CDC13) 5 0.58-0.66 (m, 6H, Si-CH2); 0.91-0.99 (t, .7=8.7, 9H, CH2CH3); 1.24 (s, 3H, 17-Me); 1.28 (s, 3H, 16,-Me); 1.75 (s, 3H, 19-Me); 1.83-2.05 (m, IH, 6-H); 2.14 (s, 3H, 18-Me); 2.24 (s, 3H, 10-OAc); 2.26 (s, 3H, 4-OAc); 2.46-2.61 (m, IH, 6-H); 3.64 (s, IH, 1-OH) 3.73 (d, 7=1.8, IH, 14-OH); 3.87 (d, J=6.9, IH, 3-H); 4.14 (d, 7=1.8, IH, 14-H); 4.31 (s, 2H, 20-H); 4.49 (dd, 7=10.7, 6.6, IH, 7-H); 4.93 (d, 7=7.3, IH, 5-H); 5.89 (d, J= 7.0, 1H, 2-H); 6.53 (s, 1H, 10-H); 7.46-7.66 (m, 3H, Bz); 8.08 (dd, 7=7.0, 1.5.2H, Bz)
d) 14p-Hvdroxv-7-TES-13-keto-baccatinIII 1.14-carbonate A solution of 14f}-hydroxy-7-TES-13-keto-baccatin (12.2 g) in anhydrous DCM (50 ml) and pyridine (16 ml) was dropped in a 20% phosgene solution in DCM (45 mL, 5 eq) at -10°C. After 2 hours the reaction was added drop by drop with a 5% NaHC03 aqueous solution (100 ml). The aqueous layer was washed with DCM (3 x 50 ml) and the crude was purified by flash chromatography (silica gel, DCM-AcOEt=50:l) to give the title compound in a 95% yield. M.p.: 97-99°C. TLC: cHex-AcOEt 1:1, Rf=0.64. 'H-NMR (200 MHz, CDC13) 8 0.58-0.66 (m, 6H, Si-CH2); 0.91-0.99 (t, 7=8.7, 9H, CH2CH3); 1.21 (s, 3H, 17-Me); 1.39 (s, 3H, 16,-Me); 1.75 (s, 3H, 19-Me); 1.86-2.13 (m, 1H, 6-H); 2.22 (s, 3H, 18-Me); 2.25 (s, 3H, 10-OAc); 2.26 (s, 3H, 4-OAc); 2.48-2.63 (m, 1H, 6-H); 3.83 (d, 7=7.0, 1H, 3-H); 4.30 (ABq, 2H, 20-H); 4.49 (dd, 7=11.0, 7.0, IH, 7-H); 4.81 (s, 1H, 14-H); 4.93 (d, 7=7.3, 1H, 5-H); 6.15 (d, 7= 7.0, 1H, 2-H); 6.54
(s, IH, 10-H); 7.51 (t, 2H, Bz); 7.62-7.70 (m, IH, Bz); 8.01 (dd, 7-7.0, 1.9, 2H, Bz).
e) 14ß-Hvdroxv-7-TES-baccatinIII 1.14-carbonate
A suspension of NaBH4 (0.5 g) in absolute ethanol (10 ml) was cooled to -50°C, and added with a cooled solution of 14-hydroxy-7-TES-13-keto-baccatin III 1,14-p-carbonate (0.5 g, 0.6 mmol) in absolute ethanol (10 ml). After the starting product disappeared (8 h), the reaction was quenched with citric acid and extracted with AcOEt. The combined organic layers were dried over sodium sulfate and the solvent was evaporated off. The title compound was obtained as a white solid in an 85% yield, after chromatography. M.p.: 134-137°C. TLC: cHex-AcOEt 1:1, Rf=0.46. !H-NMR (200 MHz, CDC13) 6 0.58-0.66 (m, 6H, Si-CH2); 0.91-0.99 (t, .7=8.7, 9H, CH2CH3); 1.16 (s, 3H, 17-Me); 1.28 (s, 3H, 16,-Me); 1.74 (s, 3H, 19-Me); 1.85-2.14 (m, IH, 6-H); 2.06 (s, 3H, 18-Me); 2.21 (s, 3H, 10-OAc); 2.33 (s, 3H, 4-OAc); 2.47-2.65 (m, IH, 6-H); 3.74 (d, .7=7.4, IH, 3-H); 4.12-4.35 (m, 2H, 20-H); 4.49 (dd, .7=10.3, 6.6, IH, 7-H); 4.82 (d, IH, 14-H); 4.99 (d, J=7.3, IH, 5-H); 5.00-5.03 (m, IH, 13-H); 6.11 (d, J= 7.4, IH, 2-H); 6.45 (s, IH, 10-H); 7.50 (t, 2H, Bz); 7.60-7.68 (m, IH, Bz); 8.04 (dd, .7=7.0, 1.5, 2H, Bz).
f) 14ß-Hydroxv-baccatinIII 1.14-carbonate
14-Hydroxy-7-TES-baccatin III 1,14-p-carbonate (9.6 g, 1.3 mmol)
was dissolved in a mixture of acetonitrile (5.4 ml) and pyridine (6.4 ml) cooled to 0°C. A solution of 70% HF in pyridine (0.95 ml) was dropped in 15 min and the solution was stirred at room temperature overnight. The reaction mixture was then poured into 20 mL of ice and left under stirring for 1 h, then extracted with DCM (3 x 10 ml) and the combined organic layers were washed with 10% NaHSO4 (to pH=2), 5% NaHC03 (2x10 ml) and brine (2x10 ml). After evaporation of the solvent, the title compound
was obtained as a white solid in a 96% yield.

CLAIMS
1. A process for the preparation of 14p-hydroxy-l,14-carbonate-baccatin
III, which comprises:
a. treatment of 7-triethylsilyl-13-ketobaccatin III of formula

(Formula Removed)
with suitable bases and oxidizing agents, to give 7-triethylsilyl-13-keto-14-hydroxy-baccatin III:
(Formula Removed)
b. carbonation of the 1 and 14 hydroxyls to give 14p-Hydroxy-7-TES-13-keto-baccatin III-l,14-carbonate:
(Formula Removed)c. reduction of the ketone at the 13- position and cleavage of the protective group in 7.
2. A process as claimed in claim 1 wherein step a) is carried out by treatment with potassium t-butoxide or potassium bis(trimethylsilyl)amide at a temperature from -40 to -78°C in ethers in admixture with
hexamethylphosphoramide (HMPA) or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone (DMPU), in the presence of oxaziridine derivatives.
3. A process as claimed in claim 2 wherein the oxaziridine derivative is
selected from N-benzenesulfonyl phenyl oxaziridine, N-benzenesulfonyl m-
nitrophenyl oxaziridine and camphorsulfonyloxaziridine.
4. A process as claimed in any one of claims 1 to 3, wherein step h) is
carried out by treatment with a carbonyldiimidazole or phosgene in
chlorinated solvents in the presence of a base at temperatures ranging from
-40°C to room temperature.
5. A process as claimed in any one of claims 1 to 4, wherein step c) is
carried out by treatment with a hydride at a temperature from -20 to -50°C.
6. A process as claimed in claim 5 wherein the hydride is selected from
sodium borohydride, lithium borohydride, sodium triacetoxy borohydride
and the reaction is carried out in ethanol, methanol, isopropanol, or in a
methanol and tetrahydrofuran mixture.
7. A process as claimed in any one of claims 1 to 6 wherein 13-keto-
baccatin III protected at the hydroxyl in 7 is prepared by selective
acetylation of the hydroxyl 10 followed by oxidation of the hydroxyl 13 and
protection of the hydroxyl 7.
8. A process as claimed in claim 7 wherein 13-keto-baccatin III is obtained
by selective acetylation of deacetylbaccatin III in 10 with acetic anhydride
followed by oxidation with manganese dioxide in aprotic solvents at 0°C - 60°C.
9. As a novel intermediate, the compound 7-triethylsilyl-13-keto-14-
(Formula Removed)
hydroxy-baccatin III, of formula
10. As a novel intermediate, the compound 14p-Hydroxy-7-TES-13-keto-
baccatin 111-1,14-carbonate, of formula :
(Formula Removed)
11. A process for the preparation of 14ß-hydroxy-l, 14-carbonate-baccatin III substantially as herein described with reference to the foregoing description and the accompanying example.
12. Novel intermediate, the compound 7-triethylsilyl-13-keto-14-
hydroxy-baccatin III substantially as herein described with reference to the foregoing description and the accompanying example.

13. Novel intermediate, thecompound 14ß-Hydroxy -7-TES-13-keto-baccatin III substantially as herein described with reference to the foregoing description and the accompanying example.

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Patent Number

268238

Indian Patent Application Number

951/DELNP/2004

PG Journal Number

35/2015

Publication Date

28-Aug-2015

Grant Date

22-Aug-2015

Date of Filing

12-Apr-2004

Name of Patentee

INDENA S.P.A.

Applicant Address

VIALE ORTLES, 12, I-20139 MILANO, ITALY.

Inventors:

#	Inventor's Name	Inventor's Address
1	NA	NA
2	BOMBARDELLI , EZIO	VIA VAL DI, SOLE, 22, I-20141, MILANO, ITALY.
3	FONTANA, GABRIELE	VIALE ORTLES, 12, I-20139 MILANO, ITALY.
4	GELMI, MARIA, LUISA	UNIVERSITA DEGLI STUDI DI MILANO, INSTITUTO DI CHIMICA ORGANICA - FACOLTA DI FARMACIA, VIA VENEZIAN, 21, I-20133, MILANO, ITALY.
5	POCAR, DONATO	UNIVERSITA DEGLI STUDI DI MILANO, INSTITUTO DI CHIMICA ORGANICA - FACOLTA DI FARMACIA, VIA VENEZIAN, 21, I-20133, MILANO, ITALY.

PCT International Classification Number

A61K 31/335

PCT International Application Number

PCT/EP02/08005

PCT International Filing date

2002-07-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI2001A002186	2001-10-19	Italy