HK1069170B - A process for the preparation of the 14beta-hydroxy-baccatin iii-1, 14-carbonate - Google Patents

Description

Process for the preparation of 14 beta-hydroxy-baccatin III-1, 14-carbonate

the present invention relates to a process for the preparation of 14 beta-hydroxy-1, 14-carbonate-baccatin III. The product obtained by the method of the invention can be used for preparing novel taxane derivatives with anti-tumor activity.

Taxanes are one of the most important classes of antineoplastic agents developed in recent years. Paclitaxel is a diterpene complex obtained from the bark of Taxus brevifolia (Taxus brevifolia), and is considered as one of the major drugs for treating cancer. At present, new taxane derivatives having higher pharmacological activity and improved pharmacokinetic profile are being widely sought. One particular approach involves baccatin III derivatives with various modifications to the parent structure. Examples of such compounds are represented by the 14 β -hydroxybaccatin III derivatives disclosed in US 5705508, WO97/43291, WO 96/36622. At present, 14 β -hydroxy-deacetylbaccatin III 1, 14-carbonate derivatives are prepared starting from the precursor 14 β -hydroxy-deacetylbaccatin III, a natural compound which is obtainable in small amounts by extraction of the leaves of Taxus wallichiana (Taxus wallichiana), as described in EP 559019. There is a great need for a new process for the easy and efficient preparation of large quantities of 14 β -hydroxy-1, 14-carbonate-baccatin III and thus of large quantities of its derivatives.

It has now been found that 14 β -hydroxy-baccatin III-1, 14-carbonate can be prepared by a process starting from 13-ketobaccatin III, which is readily obtainable from 10-deacetylbaccatin III, whereas 10-deacetylbaccatin III, in contrast to 14 β -hydroxy-baccatin III, can be readily isolated in large amounts from the leaves of Taxus baccata (Taxus baccata).

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

a. treating 7-triethylsilyl-13-ketobaccatin III of the formula,

to give 7-triethylsilyl-13-keto-14-hydroxy-baccatin III:

b. carbonating the hydroxyl groups in positions 1 and 14 to form 14 β -hydroxy-7-triethylsilyl-13-keto-baccatin III-1, 14-carbonate:

c. the ketone at position 13 is reduced and the protecting group at position 7 is cleaved.

The starting 13-ketobaccatin III is conveniently protected at the 7-position with a suitable protecting group, preferably selected from silyl ethers (preferably triethylsilyl ether). Step a) is carried out by treatment with a suitable base, in particular potassium tert-butoxide (t-BuOK) or potassium bis (trimethylsilyl) amide (KHMDS). The reaction may be carried out at-40 to-78 ℃. Suitable solvents for this reaction are ethers, such as tetrahydrofuran or diethyl ether, in particular ethers mixed with Hexamethylphosphoramide (HMPA) or 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) pyrimidinone (DMPU). The enolate is then treated with an oxidizing agent such as oxaziridine derivatives (particularly N-phenylsulfonylphenylazepine, N-phenylsulfonyl-m-nitrophenyloxy-aziridine and camphorsulfonyloxaziridine) to provide 7-protected 13-keto-14-hydroxy-baccatin III derivatives.

Step b) is then carried out by treatment with a carbonylation reagent (e.g. carbonyldiimidazole or phosgene) under conditions generally described in the literature to provide the 1, 14-carbonate derivative. The reaction is conveniently carried out in an inert solvent, preferably an ether or chlorinated solvent, in the presence of a base, preferably pyridine or triethylamine, at a temperature in the range from-40 ℃ to room temperature. The reaction can be carried out either with the pure starting materials or with the crude product of the previous step.

The reduction of the carbonyl group in position 13 in step c) is easily accomplished with sodium borohydride in ethanol at a temperature generally in the range of-20 to-50 deg.c, the reaction being completed in 2-6 hours. The reaction can also be carried out in methanol, isopropanol, or in a mixture of methanol and tetrahydrofuran. The reducing agent may be used in stoichiometric amounts, although it is preferred to use an excess of hydride. Reduction can also be achieved with other hydrides under conditions known in the art, preferably tetrabutylammonium borohydride, lithium borohydride, sodium triacetoxyborohydride.

Depending on the protecting group used, the protection at position 7 is removed under different conditions. For example, if the protecting group at the 7-position is triethylsilyl ether, hydrolysis with hydrochloric acid in methanol or hydrofluoric acid and pyridine in acetonitrile can be successfully used.

13-keto-baccatin III is conveniently prepared by oxidation of baccatin III. The oxidation of baccatin III can be carried out with ozone, or with manganese dioxide in aprotic solvents such as dichloromethane, tetrahydrofuran, acetone, ethyl acetate. The reaction can be carried out at 0 ℃ to 60 ℃, more preferably at room temperature.

The method of the invention is summarized in the following figures:

the following examples further illustrate the invention.

The abbreviations used are as follows:

AcOEt ═ ethyl acetate; TES ═ triethylsilyl; TESCl ═ triethylchlorosilane; DCM ═ dichloromethane; THF ═ tetrahydrofuran.

Examples

a) 13-keto-baccatin III

Baccatin III (150g, 0.25mol) was dissolved in acetone (1.43L). Commercial manganese dioxide (450g) was added in three portions with vigorous stirring. After disappearance of the starting product (4 hours), the suspension is filtered and the solvent is distilled off. The crude product was suspended in AcOEt (100ml) and refluxed for 1 hour, then cyclohexane (100ml) was added. After evaporation of the solvent, the title compound was obtained as a white solid from the mother liquor (140g, 95%).

b) 7-TES-13-keto-baccatin III

13-keto-baccatin III (5g, 8.5mmol), TESCl (3.6mL, 21.4mmol, 2.5 equivalents), and N-methylimidazole (2.73mL, 34.3mmol, 4 equivalents) were dissolved in anhydrous DCM (25 mL). The solution was left under stirring for 1.5 hours, after which it was poured slowly into 2M NaHSO₄The reaction was terminated in (25 ml). The aqueous layer was washed with DCM (2X 10ml), extracted and the combined organic layers were extracted with brine (2X 20 ml). Dried with sodium sulfateThe organic solution was dried to give 4.7g of the title compound in a purity sufficient for the subsequent step. M.p.: 212 deg.C. TLC: cHex-AcOEt 1: 1, Rf 0.57.¹H-NMR(200MHz，CDCl₃)δ0.58-0.66(m，6H，Si-CH₂)；0.90-0.98(t，J＝8.4，9H，CH₂CH₃)；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＝7.7，1H，5-H)；5.72(d，J＝7.0，1H，2-H)；6.61(s，1H，10-H)；7.52(t，J＝6.2，2H，Bz)；7.64(t，J＝6.2，1H，Bz)；8.10(dd，J＝7.4，1.1，2H，Bz)。

c) 14-hydroxy-7-TES-13-keto-baccatin III

In N₂Next, 7-TES-13-keto-baccatin III (670mg, 0.96mmol) was dissolved in a mixture of anhydrous THF (9ml) and DMPU (2ml) and cooled to-60 ℃. 1M t-BuOK in THF (2.5ml, 0.86mmol) pre-cooled to-50 ℃ was added dropwise thereto. The solution was stirred at-60 ℃ for 45 minutes, then (. + -.) -camphorsulfonyl-oxazepine (440mg, 2mmol) dissolved in anhydrous THF (2ml) was added dropwise. The reaction mixture was stirred at-60 ℃ for 3 hours, after which the reaction was quenched with 10% AcOH in dry THF (2 ml). The mixture was then allowed to warm at room temperature before extraction with DCM (2 × 10 ml). The combined organic layers were washed with water, saturated aqueous NaCl solution (15ml), and Na₂SO₄And (5) drying. The title compound was purified by flash chromatography (silica gel, cHex-AcOEt, 8: 2) in 79% yield. Alternatively, the compound was used directly in the subsequent step without further purification. M.p.: 94-98 ℃. TLC: cHex-AcOEt 1: 1, Rf 0.5.¹H-NMR(200MHz，CDCl₃)δ0.58-0.66(m，6H，Si-CH₂)；0.91-0.99(t，J＝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，1H，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，1H，6-H)；3.64(s，1H，1-OH)；3.73(d，J＝1.8，1H，14-OH)；3.87(d，J＝6.9，1H，3-H)；4.14(d，J＝1.8，1H，14-H)；4.31(s，2H，20-H)；4.49(dd，J＝10.7，6.6，1H，7-H)；4.93(d，J＝7.3，1H，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，J＝7.0，1.5，2H，Bz)。

d)14 beta-hydroxy-7-TES-13-keto-baccatin III 1, 14-carbonate

A solution of 14 β -hydroxy-7-TES-13-keto-baccatin (12.2g) in dry DCM (50mL) and pyridine (16mL) was added dropwise to a 20% solution of phosgene in DCM (45mL, 5 equivalents) at-10 ℃. After 2 hours, 5% NaHCO was added dropwise to the reaction₃Aqueous solution (100 ml). The aqueous layer was washed with DCM (3 × 50ml) and the crude product was purified by flash chromatography (silica gel, DCM-AcOEt ═ 50: 1) to give the title compound in 95% yield. M.p.: 97-99 ℃. TLC: cHex-AcOEt 1: 1, Rf 0.64.¹H-NMR(200MHz，CDCl₃)δ0.58-0.66(m，6H，Si-CH₂)；0.91-0.99(t，J＝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，J＝7.0，1H，3-H)；4.30(ABq，2H，20-H)；4.49(dd，J＝11.0，7.0，1H，7-H)；4.81(s，1H，14-H)；4.93(d，J＝7.3，1H，5-H)；6.15(d，J＝7.0，1H，2-H)；6.54(s，1H，10-H)；7.51(t，2H，Bz)；7.62-7.70(m，1H，Bz)；8.01(dd，J＝7.0，1.9，2H，Bz)。

e)14 beta-hydroxy-7-TES-baccatin III 1, 14-carbonate

Reacting NaBH₄(0.5g) of the suspension in anhydrous ethanol (10ml) was cooled to-50 ℃ and a cooled solution of 14-hydroxy-7-TES-13-keto-baccatin III 1, 14-. beta. -carbonate (0.5g, 0.6mmol) in anhydrous ethanol (10ml) was added. After disappearance of the starting product (8 hours)At time), 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. The title compound was obtained as a white solid after chromatography in 85% yield. M.p.: 134 ℃ and 137 ℃. TLC: cHex-AcOEt 1: 1, Rf 0.46.¹H-NMR(200MHz，CDCl₃)δ0.58-0.66(m，6H，Si-CH₂)；0.91-0.99(t，J＝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，1H，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，1H，6-H)；3.74(d，J＝7.4，1H，3-H)；4.12-4.35(m，2H，20-H)；4.49(dd，J＝10.3，6.6，1H，7-H)；4.82(d，1H，14-H)；4.99(d，J＝7.3，1H，5-H)；5.00-5.03(m，1H，13-H)；6.11(d，J＝7.4，1H，2-H)；6.45(s，1H，10-H)；7.50(t，2H，Bz)；7.60-7.68(m，1H，Bz)；8.04(dd，J＝7.0，1.5，2H，Bz)。

f)14 beta-hydroxy-baccatin III 1, 14-carbonate

14-hydroxy-7-TES-baccatin III 1, 14-beta-carbonate (9.6g, 1.3mmol) was dissolved in a mixture of acetonitrile (5.4ml) and pyridine (6.4ml) cooled to 0 ℃. A 70% solution of HF in pyridine (0.95ml) was added dropwise over 15 minutes, and the solution was stirred at room temperature overnight. The reaction mixture was then poured into 20mL of ice and left under stirring for 1 hour, then extracted with DCM (3 × 10mL) and extracted with 10% NaHSO₄(to pH 2), 5% NaHCO₃The combined organic layers were washed (2X 10ml) and brine (2X 10 ml). After evaporation of the solvent, the title compound was obtained as a white solid in 96% yield.

Claims (8)

1. A process for preparing 14 β -hydroxy-1, 14-carbonate-baccatin III comprising:

a. treating 7-triethylsilyl-13-ketobaccatin III of formula with potassium tert-butoxide or potassium bis (trimethylsilyl) amide in an ether mixed with hexamethylphosphoramide or 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) pyrimidinone in the presence of an oxaziridine derivative at a temperature of from-40 to-78 ℃,

to give 7-triethylsilyl-13-keto-14-hydroxy-baccatin III:

b. carbonating the hydroxyl groups at positions 1 and 14 to form 14 beta-hydroxy-7-TES-13-keto-baccatin III-1, 14-carbonate:

c. the ketone at position 13 is reduced and the protecting group at position 7 is cleaved.

2. The method of claim 1, wherein the oxaziridine derivative is selected from the group consisting of N-benzenesulfonylphenyloxaziridine, N-benzenesulfonyl m-nitrophenyloxaziridine and camphorsulfonyl oxaziridine.

3. The process according to any one of claims 1 to 2, wherein step b) is carried out by treatment with carbonyldiimidazole or phosgene in chlorinated solvents in the presence of pyridine or triethylamine at a temperature ranging from-40 ℃ to room temperature.

4. The process according to any one of claims 1 to 2, wherein step c) is carried out by treatment with a hydride at a temperature from-20 to-50 ℃, wherein said hydride is selected from sodium borohydride, lithium borohydride, sodium triacetoxyborohydride.

5. The process of claim 4, wherein the reaction is carried out in ethanol, methanol, isopropanol, or in a mixture of methanol and tetrahydrofuran.

6. The process according to any one of claims 1 to 2 wherein the 13-keto-baccatin III protected by the hydroxyl group at the 7-position is prepared by selective acetylation of the hydroxyl group at the 10-position followed by oxidation of the hydroxyl group at the 13-position and protection of the hydroxyl group at the 7-position.

7. A process according to claim 6 wherein 13-keto-baccatin III is obtained by selective acetylation of deacetylbaccatin III at the 10-position with acetic anhydride, followed by oxidation with manganese dioxide in an aprotic solvent at 0 ℃ to 60 ℃.

8. As a novel intermediate the compound 14 β -hydroxy-7-TES-13-keto-baccatin III-1, 14-carbonate of the formula: