Cabazitaxel, related compounds and methods of synthesis

Abstract

The invention provides new cabazitaxel isoserine ester intermediates and new synthetic methods, and a preparation method for the anti-tumour drugs cabazitaxel, docetaxel and paclitaxel from the new cabazitaxel isoserine intermediates.

Claims

1. A method of preparing a taxane product compound from a protected taxane intermediate, the method comprising reacting the protected taxane intermediate with a reducing agent and a Lewis acid wherein the protected taxane intermediate has the formula V: ##STR00032## and the taxane compound has the formula IV, ##STR00033## the method further comprising: a.) reacting the taxane compound of formula IV ##STR00034## with a strong base to obtain a corresponding metallated compound VI ##STR00035## and b.) reacting the metallated compound VI with methyl iodide or dimethyl sulphate to obtain compound III; ##STR00036## wherein R1 is a hydroxy protecting group; and wherein M is selected from the group consisting of a IA, IIA, IIIA, IVA, VA, VIA group element or a transition metal, zinc, and calcium.

2. The method of claim 1, wherein the strong base is selected from the group consisting of sodium methoxide, sodium amide, sodium hydride, n-butyl-lithium, lithium bi(trimethyl silyl)amino and sodium hexamethyl bisilyl amino.

3. The method of claim 1, further comprising deprotecting the R1 protecting group from compound III ##STR00037## to obtain cabazitaxel ##STR00038##

4. The method of claim 3, wherein the method is carried out by deprotecting the protecting group R1 in acid solvent, the acid being selected from formic acid, acetic acid, hydrofluoric acid, hydrochloric acid, p-methyl-benzene monosulfonic acid, and mixtures thereof.

5. The method of claim 1, wherein M is sodium, potassium, lithium, zinc, or calcium.

6. The method of claim 2, wherein the strong base is selected from the group consisting of sodium hydride and n-butyl-lithium.

7. The method of claim 4, wherein the acid is hydrochloric acid or hydrofluoric acid, and wherein the solvent is water, organic solvent, or organic solvent with water.

Description

(1) The invention is illustrated by Figures in which:

(2) FIG. 1 depicts a first method of preparing cabazitaxel according to the invention;

(3) FIG. 2 depicts a second method of preparing cabazitaxel according to the invention;

(4) FIG. 3 depicts further reaction schemes according to the invention; and

(5) FIG. 4 depicts a prior art synthesis of taxane derivatives starting from 9-DHB.

DETAILED DESCRIPTION

(6) The invention provides a new method for the preparation of cabazitaxel, one embodiment of which can be summarized as follows, showing the preparation of a protected taxane intermediate and its deprotection to taxane compounds:

(7) ##STR00023## ##STR00024##

(8) This reaction is also depicted in FIG. 1. The reaction of the invention reduces the number of steps and increases yield of cabazitaxel.

(9) The deprotection methods of the invention can also be used for the preparation of paclitaxel (taxol):

(10) ##STR00025##

(11) The deprotection methods of the invention can also be applied to the preparation of docetaxel:

(12) ##STR00026##
10-DAB Synthetic Routes

(13) A first synthetic pathway of the invention can be summarized as follows, as illustrated above, wherein steps (a) and (b) are known in the art for example from WO 2006/004708, WO 2008/032104 and EP 2 003 124 A1. a) Starting from 10-DAB (compound II), selectively protect the 7 and 10 positions of the molecule with an OH-protecting group such as TROC (trichloroethoxycarbonyl groups); b) Couple the protected 10-DAB analogue at the 13 position to a phenylisoserine side-chain precursor (a beta-lactam) protected by a suitable hydroxy protecting group R1 at the 2-position such that the resulting 7,10-protected C-13 substituted taxane intermediate (compound V) has an R1 hydroxy protecting group at the 2-position on the phenylisoserine side chain; c) Deprotect at the 7 and 10 positions using a reducing agent and a Lewis acid to yield 7,10-hydroxy compound (IV); d) Methylate at the 7 and 10 positions to provide novel ester III; and e) Deprotect the R1 group to yield cabazitaxel (I).

(14) To produce docetaxel, one simply needs to omit the methylation step (d) above, since docetaxel is a hydroxy analogue of cabazitaxel.

(15) Processes for the side-chain condensation reaction have been described in the art, for example in WO 2008/090368 and WO2004033442. Such techniques are suitable for the side-chain addition reactions mentioned herein and depicted in the reaction schemes of this disclosure.

(16) Paclitaxel may also be produced using the same methodology, starting from 9-dihydro-13-acetylbaccatin III (9-DHB) instead of 10-DAB and noting that just one selective protection is necessary at step a.

(17) An important intermediate of the above synthetic pathways is the novel taxol isoserine ester or its salt (formula III):

(18) ##STR00027##

(19) In compound III, the moiety R1 is hydroxy (or hydroxyl) protecting group.

(20) The hydroxy protecting group is any group which can protect hydroxy. It should be a group that remains stable during reaction and after reaction, and can be removed to deprotect without destroying any other structure of the molecule. These kinds of group can be found in the following reference The protecting groups in organic synthesis (T. W. Greene, East China University of Science & Technology publisher) and Protecting groups (P. Kocienski, Thieme Publisher). In this invention, the hydroxy protecting group can be any hydroxy protecting group, as understood by a skilled person.

(21) In the method of the invention, R1 is a hydroxy protecting group which can be deprotected in acidic, basic or neutral pH.

(22) In an example at the invention, R1 is benzyloxy-carbonyl, tert-butyloxy-carbonyl, trichloro-acetyl, trifluoro-acetyl, 1-ethoxy-ethyl, methoxy-iso-propanyl, tri-ethylsilyl (TES), or trimethyl silyl (TMS), furanidinyl, tert-butyl-bimethylsilyl (TBS), tert-butyl-biphenylsilyl (TBDIPS), optimal protecting group is 1-ethoxy-ethyl (EE), tri-ethylsilyl (TES), tetrahydropyrane (THP) or tert-butyl-bimethyl silyl (TBS).

(23) A further important novel taxel isoserine ester or its salt, involved as an intermediate in the methodologies of the invention, has the compound number IV:

(24) ##STR00028##
R1 is the hydroxyl protecting group mentioned above for compound III.
Preparation of Compound IV (Step c Above)

(25) Compound IV can be obtained in the art by zinc powder reduction methods to selectively deprotect the trichloroethoxycarbonyl groups (TROC groups) from compound V. Preparation of compound V can be found in the reference Bioorganic & Medicinal Chemistry Letters, Vol 13, No. 11, 2419-2482, 1993.

(26) ##STR00029##

(27) In formula V, R1 is a hydroxyl protecting group as outlined above for formula III, or hydrogen.

(28) In the published reports, trichloroethoxycarbonyl (TROC) can be deprotected in the presence of zinc powder in acetic acid.

(29) If R1 is more or less stable in acetic acid, then acetic acid deprotection may also be used to selectively deprotect trichloroethoxycarbonyl (TROC), for example when R1 is triethylsilyl, tert-butyl-bimethyl silyl (TBS) and tert-butyl-biphenyl silyl. However due to the presence of acetic acid, a small proportion of the protecting group at R1 is expected to also be deprotected. The yield of compound IV is therefore decreased and work-up of the reaction is difficult due to side products.

(30) The invention provides a novel method to deprotect trichloroethoxycarbonyl (TROC).

(31) In the invention, acetic acid is replaced by a Lewis acid and the solvent is preferably a polar solvent or solvent containing polarity. Under these conditions, R1 can be any hydroxyl protecting group, including acid-sensitive groups, such as tetrahydropyrone (THP) or 1-ethoxy-ethyl.

(32) Polar solvents include but are not limited to all alcohols, acetone, tetrahydrofuran, acetonitrile and water.

(33) The reducing agent can be any reducing agent known in the art, but preferably a metal-based reducing agent including metals such as zinc, potassium, calcium, barium, sodium and magnesium and metal hydrides such as NaH, LiH, LiAlH.sub.4 and CaH.sub.2. The reducing agent may be in the form of a powder.

(34) A Lewis acid can be defined in the art as an electron pair (lone pair) acceptor, i.e. an entity that can accept a pair of electrons to complete its stable electronic configuration. Lewis acids include but are not limited to ammonium chloride, ammonium sulfate, ammonium acetate, zinc chloride, magnesium chloride and calcium chloride.

(35) Optionally, the deprotection reaction can occur in a solvent containing lower alkyl alcohol or water in the presence of zinc powder and ammonium chloride. A lower alkyl alcohol, as defined in this specification, is a C1, C2, C3, C4 or C5 straight chain or branched alkyl alcohol such as methanol, ethanol or propanol.

(36) The TROC deprotection reaction of the invention is typically carried out at 100 to 75 degrees C., preferably 10 to 50 degrees C. and more preferably 5 to 10 degrees C.

(37) The reaction time for the invention can be 1 minute to 24 hrs, or more preferably 2 minutes to 12 hrs, even more preferably 3 minutes to 6 hrs, and most preferably 30 minutes to 2 hrs.

(38) The reaction is preferably carried under nitrogen or argon or other noble gas or another inert gas.

(39) The inventive method of deprotecting trichloroethoxycarbonyl (TROC) in the reaction is not only useful for preparation of cabazitaxel, but also for preparation of docetaxel and paclitaxel.

(40) Preparation of Compound III (Step d)

(41) The inventive method of the invention includes reacting compound IV with a base to obtain intermediate metallated compound VI

(42) ##STR00030##
M is a group IA, IIA, IIIA, IVA, VA, VIA metal or transition metal, zinc or calcium

(43) In the method of the invention, the base is an inorganic base metal base or organic base metal base.

(44) Preferably the base is sodium methoxide, sodium amide, sodium hydride, lithium n-butyl, lithium bi(trimethyl silyl)amino or sodium hexamethyl bisilyl amino.

(45) The reaction of the invention is typically carried out at 100 to 75 degrees C., preferably 10 to 50 degrees C. and more preferably 5 to 10 degrees C.

(46) The reaction time for the invention can be 1 minute to 24 hrs, or more preferably 2 minutes to 12 hrs, even more preferably 3 minutes to 6 hrs, and most preferably 30 minutes to 2 hrs.

(47) The reaction is preferably carried in the absence of water and oxygen, under nitrogen or argon or other noble gas or another inert gas.

(48) Compound VI is subsequently reacted with methyl iodide (MeI) or dimethyl sulfate (Me).sub.2SO.sub.4 to obtain compound III via a methylation reaction, replacing the metals M with methyl groups.

(49) Preparation of Cabazitaxel from Compound III (Step e)

(50) Compound III is deprotected at the R1 position preferably in aqueous solution having pH 1 to 9.

(51) Preferably the above R1 deprotection reaction is in acid solution wherein the acid is formic acid, acetic acid, hydrofluoric acid, hydrochloric acid, p-methylphenyl sulfonic acid or a mixture thereof. Preferably the acid is hydrochloric acid or hydrofluoric acid, the solution is aqueous solution, organic solution or mixed aqueous-organic solution.

(52) In a method of the invention, the above R1 deprotection reaction is carried out at 50 to 100 degrees C., preferably 30 to 60 degrees C., or most preferably 10 to 20 degrees C.

(53) The R1 deprotection reaction is carried out for example for 0.5 hr to 80 hrs, preferably 1 hr to 60 hrs, or more preferably 2 hrs to 50 hrs.

(54) Preparation of Docetaxel Directly from Compound IV

(55) An equivalent R1 deprotection reaction as step (e) above can be used to prepare docetaxel directly from compound IV. Preferably the deprotection is carried out in aqueous solution having pH 1 to 9.

(56) Preferably the above deprotection reaction is in acid solution wherein the acid is formic acid, acetic acid, hydrofluoric acid, hydrochloric acid, p-methylphenyl sulfonic acid or a mixture thereof. Preferably the acid is hydrochloric acid or hydrofluoric acid, the solution is aqueous solution, organic solution or mixed aqueous-organic solution.

(57) In a method of the invention, the above deprotection reaction is carried out at 50 to 100 degrees C., preferably 30 to 60 degrees C., or most preferably 10 to 20 degrees C.

(58) The deprotection reaction is carried out for example for 0.5 hr to 80 hrs, preferably 1 hr to 60 hrs, or more preferably 2 hrs to 50 hrs.

(59) 9-DHB Synthetic Routes

(60) The above methods start from the taxane compound 10-deacetylbaccatin (10-DAB), derived from Taxus plant species. In addition, it is possible to adopt the same or equivalent synthetic strategies to produce cabazitaxel starting from a different taxoid starting material, namely 9-dihydro-13-acetylbaccatin III (9-DHB), present in another Taxus species, namely the Canadian yew (Taxus Canadensis).

(61) ##STR00031##

(62) The equivalent 9-DHB synthetic methods may be summarized as follows, and are depicted in FIG. 2: 1. Starting from 9-DHB, protect the 7 position with methoxy (OMe); 2. Deprotect the resultant 7-protected 9-DHB at the C10 and C13 positions to yield 7-OMe-10,13-deacetyl-9DHB; 3. Oxidize at 9-position to give 7-OMe-10DAB, i.e introduce a keto group at the 9-position; 4. Couple the 7-protected 10-DAB analogue at the 13 position to a phenylisoserine side-chain precursor (a beta-lactam) protected by a suitable hydroxy protecting group R1 at the 2-position such that the resulting 7-protected C-13 substituted taxane intermediate has an R1 hydroxy protecting group at the 2-position on the phenylisoserine side chain; 5. Methylate as described above (step d) for the 10-DAB pathway at the 10 position to provide novel ester III; and 6. Deprotect the R1 group as described above (step e) for the 10-DAB pathway to yield cabazitaxel (I).

(63) Alternatively, in the 9-DHB procedure immediately above, steps (3) and (4) may be performed in the opposite order, namely firstly coupling the phenylisoserine chain at the 13 position, then oxidizing the 9 position.

(64) Furthermore, one could reverse the order of steps (1) and (2), namely firstly deprotecting at the 10 and 13 positions to provide 7,10,13-hydroxy-9DHB, then selectively methylating at the 7 position to yield 7-OMe-10,13 deacetyl-9DHB. Then, the steps (3) to (6) are carried out as described above.

(65) FIG. 3 depicts a further synthetic scheme of the invention, again using the starting material 9DHB.

(66) In the FIG. 3 scheme, 9DHB is firstly protected using a protecting group TROC at the 7 position. This is equivalent to step (a) explained above. The 7-TROC protected 9DHB is then deprotected at the C10 and C13 positions, and is oxidized to provide the 7-TROC protected 10DAB equivalent compound.

(67) 7-TROC 10DAB can then be coupled to its phenylisoserine side chain as explained above, to yield a mono-TROC protected docetaxel analogue.

(68) Alternatively, the 7-TROC 10DAB may be further protected with TROC to yield 7,10-diTROC 10DAB which is labeled as protected taxane intermediate V above. Compound V may then be used in the pathways explained above in connection with FIG. 1, to produce cabazitaxel or docetaxel.

(69) The necessary reaction conditions for protection, deprotection, oxidation and side chain coupling to manufacture taxane intermediates starting from 9-DHB are known in the art of taxane molecule synthesis, for example in EP 2 003 124 A1. Nevertheless, FIG. 4 presents a typical synthesis for information.

(70) The invention has several advantages. The invention provides a new, simple, easy to operate method of synthesizing cabazitaxel, paclitaxel and docetaxel. The method has fewer steps, mild reaction conditions and high purity of the reaction solution. Work-up treatment is easy and the intermediates and product are obtained simply by crystallization. This simplifies the operation and the requirements for equipment and decreases the production cost. Further, the schemes described herein yield a stable solid intermediate which benefits the quality control of both intermediates and final product, especially during industrial production.

(71) The invention is illustrated by the following examples. These examples only illustrate the invention but do not restrict the invention.

EXAMPLES

(72) The following acronyms are used in the examples: TES=triethylsilyl; TROC=trichloroethoxycarbonyl, also known as trichloroethyloxycarbonyl, defined by the formula CCl.sub.3CH.sub.2OC(O); TBS=t-Butyldimethylsilyl; and THP=tetrahydropyran.

Example 1

Comparative

(73) Pour 80 ml acetic acid and 12 g active zinc powder into a reaction container, stirring evenly, increase temperature to 60-70 degrees C., add 5 g of 2-TBS-7,10-TROC-docetaxel, and stir for 5 hrs until TLC shows the reaction completion. After filtering, add 80 ml of ethyl acetate and 80 ml of water into the filter liquor, extract, wash the organic layer with 50 ml of water, saturated NaHCO.sub.3 (50 ml2), saturated NaCl (50 ml). Then dry with anhydrous Na.sub.2SO.sub.4. Filter and then evaporate the solution to gain white solid 2-TBS-Docetaxel 2.5 g (yield 81%).

(74) MS (m/z): 972 (M+Na). .sub.1HNMR (500 MHz) 0.31 (6H, m), 0.92 (9H, m), 1.13 (3H, s), 1.30 (12H, m), 1.72 (7H, m), 1.92 (4H, m), 2.18 (1H, m), 2.35 (1H, m), 2.61 (4H, m), 3.95 (1H, d), 4.21 (3H, m), 4.28 (1H, d), 4.54 (1H, s), 4.97 (1H, d), 5.21 (1H, s), 5.27 (1H, m), 5.50 (1H, m), 5.70 (1H, d), 6.31 (1H, t), 7.29 (2H, m), 7.37 (2H, t), 7.59 (1H, t), 8.11 (1H, d),

Example 2

(75) At 35 to 40 degrees C., add 50 ml of methanol, 10 g of active zinc powder, 50 ml of water and 10 g of NH.sub.4Cl into a 100 ml reaction container. Stirring evenly, then add 5 g of 2-TES-7,10-TROC-docetaxel. Stir 4 hrs until TLC shows reaction completed. After filtering, add 80 ml of ethyl acetate, 80 ml of water into filter liquor, after extracting wash the organic layer with water (50 ml), saturated NaHCO.sub.3 (50 ml2), saturated NaCl (50 ml), dry with non-aqueous Na.sub.2SO.sub.4, filter and evaporate the solution to obtain white solid, 2.8 g of 2-TES-docetaxel (yield 90%).

(76) MS (m/z): 972 (M+Na). .sub.1HNMR (500 MHz) 0.39 (6H, m), 0.78 (9H, m), 1.13 (3H, s), 1.30 (12H, m), 1.72 (7H, m), 1.92 (4H, m), 2.18 (1H, m), 2.35 (1H, m), 2.61 (4H, m), 3.95 (1H, d), 4.21 (3H, m), 4.28 (1H, d), 4.54 (1H, s), 4.97 (1H, d), 5.21 (1H, s), 5.27 (1H, m), 5.50 (1H, m), 5.70 (1H, d), 6.31 (1H, t), 7.29 (2H, m), 7.37 (2H, t), 7.59 (1H, t), 8.11 (1H, d),

Example 3

(77) At room temperature add 50 ml of ethanol, 10 g of active zinc powder and 10 g of NH.sub.4Cl into a 100 ml reaction container. Stirring evenly, add 5 g of 2-(1-ethoxyethyl)-7,10-TROC-docetaxel. Stir 1 hr until TLC shows reaction completion, filter and evaporate the filter liquor to obtain white solid, 2-(1-ethoxyethyl)-docetaxel, 3.1 g, (yield 88%).

(78) MS (m/z): 902 (M+Na). .sub.1HNMR (500 MHz) 1.13 (6H, m), 1.30 (15H, m), 1.72 (7H, m), 1.92 (4H, m), 2.18 (1H, m), 2.35 (1H, m), 2.61 (4H, m), 3.48 (2H, m), 3.95 (1H, d), 4.21 (3H, m), 4.28 (1H, d), 4.37 (1H, m), 4.54 (1H, s), 4.97 (1H, d), 5.21 (1H, s), 5.27 (1H, m), 5.50 (1H, m), 5.70 (1H, d), 6.31 (1H, t), 7.29 (2H, m), 7.37 (2H, t), 7.59 (1H, t), 8.11 (1H, d),

Example 4

(79) At room temperature add 50 ml of methanol, 8 g of active zinc powder and 8 g of NH.sub.4Cl into a 100 ml reaction container. Stirring evenly, add 5 g of 2-THP-7,10-TROC-docetaxel. Stir 1 hr until TLC shows reaction completion, filter, evaporate the filter liquor to obtain white solid 3.3 g of 2-THP-docetaxel. (yield 91%).

(80) .sub.1HNMR (500 MHz) 1.15 (6H, m), 1.42 (15H, m), 1.82 (7H, m), 1.96 (6H, m), 2.28 (5H, m), 2.38 (3H, m), 2.69 (5H, m), 3.38 (4H, m), 3.88 (1H, d), 4.25 (3H, m), 4.26 (1H, d), 4.39 (1H, m), 4.54 (1H, s), 4.97 (1H, d), 5.21 (1H, s), 5.32 (1H, m), 5.50 (1H, m), 5.72 (1H, d), 6.32 (1H, t), 7.39 (2H, m), 7.39 (2H, t), 7.61 (1H, t), 8.11 (1H, d),

Example 5

(81) At room temperature add 50 ml of methanol, 8 g of active zinc powder and 8 g of NH.sub.4Cl into a 100 ml reaction container. Stirring evenly, add 5 g of 2-TES-7,10-TROC-docetaxel. Stir 1 hr, TLC shows reaction completion, filter, evaporate to obtain white solid 3.0 g of 2-TES-docetaxel (yield 97%).

(82) The examples 1-5 show that the yield when deprotecting TROC according to the invention (example 2-5) is improved compared to current technology (example 1). Example 1 is a prior art-type acetic acid deprotection, and as well as suffering from worse yield, also has more steps than the inventive method.

Example 6

(83) Add 50 ml of tetrahydrofuran and 5 g of 2-TES-docetaxel in 100 ml reaction container, stirring evenly, decrease temperature to 10 to 5 degrees C., add 2.5 ml of 30% n-butyl lithium solution dropwise into a 100 ml reaction container, add 0.8 ml of methyl iodide dropwise at 10 to 5 degrees C. and stir 1 hr. After TLC shows reaction completed, add 80 ml of ethyl acetate and 80 ml of saturated NH.sub.4Cl solution into the reaction solution. After extracting, wash the organic layer with saturated NH.sub.4Cl (50 ml2), saturated NaCl (50 ml), then dry with non-aqueous Na.sub.2SO.sub.4, filter and evaporate the solution to obtain a light yellow viscous solid, 4.3 g of 2-TES-cabazitaxel (yield 85%).

(84) .sub.1HNMR (500 MHz) 0.38 (6H, m), 0.79 (9H, m), 1.21.3 (16H, m), 1.60 (2H, m), 1.72 (3H, m), 1.96 (3H, m), 2.04 (1, s), 2.35 (1H, m), 2.53 (3H, s), 3.31 (3H, s), 3.46 (3H, s), 3.88 (2H, m), 4.11 (1H, m), 4.19 (1H, d), 4.32 (1H, d), 4.55 (1H, s), 4.81 (1H, s), 4.97 (1H, d), 5.29 (1H, m), 5.50 (1H, m), 5.66 (1H, d), 6.31 (1H, t), 7.29 (4H, m), 7.37 (2H, t), 7.48 (2H, t), 7.59 (1H, t), 8.11 (2H, d),

Example 7

(85) Add 50 ml of methyl iodide and 5 g of 2-TBS-docetaxel into a 100 ml reaction container, stirring evenly, decrease temperature to 10 degrees C. to 5 degrees C. Add 0.26 g of 50% NaH dropwise. Stir at 10 degrees C. to 5 degrees C. for 1 hr. TLC shows the reaction completion. Add 80 ml of ethyl acetate and 80 ml of saturated NH.sub.4Cl solution, extract, wash the organic layer with saturated NH.sub.4Cl (50 ml2), saturated NaCl (50 ml), dry with anhydrous Na.sub.2SO.sub.4, filter and evaporate the solution to obtain a light yellow viscous solid 4.4 g of 2-TBS-cabazitaxel (yield 87%).

(86) .sub.1HNMR (500 MHz) 0.38 (6H, s), 0.95 (9H, s), 1.21.3 (16H, m), 1.60 (2H, m), 1.72 (3H, m), 1.96 (3H, m), 2.04 (1H, s), 2.35 (1H, m), 2.53 (3H, s), 3.31 (3H, s), 3.46 (3H, s), 3.88 (2H, m), 4.11 (1H, m), 4.19 (1H, d), 4.32 (1H, d), 4.55 (1H, s), 4.81 (1H, s), 4.97 (1H, d), 5.29 (1H, m), 5.50 (1H, m), 5.66 (1H, d), 6.31 (1H, t), 7.29 (4H, m), 7.37 (2H, t), 7.48 (2H, t), 7.59 (1H, t), 8.11 (2H, d),

Example 8

(87) Add 50 ml of methyl iodide and 5 g of 2-TES-docetaxel into a 100 ml reaction container, stirring evenly, decrease temperature to 10 degrees C. to 5 degrees C. Add 0.26 g of 50% NaH dropwise. Stir at 10 degrees C. to 5 degrees C. for 1 hr. TLC shows the reaction completion. Add 80 ml of ethyl acetate and 80 ml of saturated NH.sub.4Cl solution, extract, wash the organic layer with saturated NH.sub.4Cl (50 ml2), saturated NaCl (50 ml), dry with anhydrous Na.sub.2SO.sub.4, filter and evaporate the solution to obtain a light yellow viscous solid 4.3 g of 2-TES-cabazitaxel (yield 87%).

Example 9

(88) Add 50 ml of methyl iodide and 5 g of 2-THP-docetaxel into a 100 ml reaction container, stirring evenly, decrease temperature to 10 degrees C. to 5 degrees C. Add 0.26 g of 50% NaH dropwise. Stir at 10 degrees C. to 5 degrees C. for 1 hr. TLC shows the reaction completion. Add 80 ml of ethyl acetate and 80 ml of saturated NH.sub.4Cl solution, extract, wash the organic layer with saturated NH.sub.4Cl (50 ml2), saturated NaCl (50 ml), dry with non-aqueous Na.sub.2SO.sub.4, filter and evaporate the solution to obtain a light yellow viscous solid 4.3 g of 2-THP-cabazitaxel (yield 87%).

(89) .sub.1HNMR (500 MHz) 1.15 (6H, m), 1.42 (15H, m), 1.82 (7H, m), 1.96 (6H, m), 2.28 (5H, m), 2.38 (3H, m), 2.69 (5H, m), 3.31 (6H, m), 3.46 (3H, s), 3.88 (1H, d), 4.25 (3H, m), 4.26 (1H, d), 4.39 (1H, m), 4.54 (1H, s), 4.97 (1H, d), 5.21 (1H, s), 5.32 (1H, m), 5.50 (1H, m), 5.72 (1H, d), 6.32 (1H, t), 7.39 (2H, m), 7.39 (2H, t), 7.61 (1H, t), 8.11 (1H, d),

Example 10

(90) Add 50 ml of tetrahydrofuran, 1 ml of dimethyl sulfate and 5 g of 2-THP-docetaxel in a 100 ml reaction container, stirring evenly, decrease temperature to 10 to 5 degrees C., add 0.26 g of 30% sodium methoxide in methanol solution dropwise, stir at 10 to 5 degrees C. for 1 hr. TLC shows reaction completed. Add 80 ml of ethyl acetate and 80 ml of saturated NH.sub.4Cl solution into the reaction solution, extract, wash organic layer with saturated NH.sub.4Cl (50 ml2), saturated NaCl (50 ml), dry with anhydrous Na.sub.2SO.sub.4, filter and evaporate the solution to obtain light yellow viscous solid, 45.1 g of 2-THP-cabazitaxel (yield 90%).

Example 11

(91) 2-(1-ethoxy-ethyl)-cabazitaxel preparation is the same as Example 10 (yield 88%).

(92) .sub.1HNMR (500 MHz) 1.13 (6H, m), 1.30 (15H, m), 1.72 (7H, m), 1.92 (4H, m), 2.18 (1H, m) 2.35 (1H, m) 2.61 (4H, m), 3.31 (3H, s), 3.46 (5H, m), 3.95 (1H, d), 4.21 (3H, m), 4.28 (1H, d), 4.37 (1H, m), 4.54 (1H, s), 4.97 (1H, d), 5.21 (1H, s), 5.27 (1H, m), 5.50 (1H, m), 5.70 (1H, d), 6.31 (1H, t), 7.29 (2H, m), 7.37 (2H, t), 7.59 (1H, t), 8.11 (1H, d),

Example 12

(93) Dissolve 100 g of 2-THP-cabazitaxel in 1730 ml of HOAc/H.sub.2O/THF (3:1:1), under N.sub.2 atmosphere, increase temperature to 50 degrees C. and stir 4 hrs. Then cool to room temperature. Add 2 L of ethyl acetate, 2 L of H.sub.2O, stir, separate layers, wash organic layer with saturated NaHCO.sub.3 (3 L2), saturated NaCl (3 L), dry with Na.sub.2SO.sub.4. Concentrate to obtain white 77.8 g of cabazitaxel (yield 83%).

(94) MS (m/z): 859 (M+Na). .sub.1HNMR (500 MHz) 1.21 (6H, d), 1.36 (9H, s), 1.59 (1H, s), 1.64 (1H, s), 1.79 (1H, m), 1.87 (3H, s), 2.27 (2H, m), 2.35 (3H, m), 2.69 (1H, m), 3.30 (3H, s), 3.45 (3H, s), 3.85 (2H, m), 4.16 (1H, d), 4.29 (1H, d), 4.62 (1H, bs), 4.79 (1H, s), 5.29 (1H, m), 5.42 (1H, d), 5.62 (1H, d), 6.21 (1H, t), 7.27.4 (6H, m), 7.48 (2H, t), 7.59 (1H, t), 8.11 (2H, d),

Example 13

(95) Dissolve 100 g of 2-TES-cabazitaxel in 10 L of acetonitrile, add 650 ml of pyridine, decrease temperature to 8 degrees C., add 1.5 L of hydrofluoric acid dropwise while keeping reaction temperature at or below 3 degrees C. (about 90 minutes). After addition is complete, keep at 0 degrees C. for 22 hrs.

(96) Add 10 L of ethyl acetate to the reaction solution for dilution, then wash with 1 N hydrochloric acid, extract aqueous layer with 10 L non-aqueous ethyl acetate, combine organic layers, wash with saturated NaHCO.sub.3 (10 L5), saturated NaCl (3.5 L1). Dry with anyhydrous Na.sub.2SO.sub.4 then concentrate under reduced pressure (<35 degrees C.) to dry to obtain 85.1 g of cabazitaxel (yield 97%).

Example 14

(97) Dissolve 100 g of 2-(1-ethoxyethyl)-cabazitaxel in tetrahydrofuran, add 1 L of ethanol, decrease temperature to 8 degrees C. Add 2N hydrochloric acid (200 ml) dropwise, while keeping the reaction temperature at or below 3 degrees C. (about 90 minutes). After addition, keep at 0 degrees C. for 22 hrs.

(98) Add 24 L of ethyl acetate into the reaction solution to dilute, then wash with 1 N hydrochloric acid (20 L2), extract aqueous phase with 10 L anhydrous ethyl acetate, combine organic layers, wash with saturated NaHCO.sub.3 (20 L5), saturated NaCl (7.5 L1). Dry with anhydrous Na.sub.2SO.sub.4 then concentrate under reduced pressure (<35 degrees C.) to dry to obtain 83.2 g of cabazitaxel (yield 95%).

Example 15

(99) Synthesis method of cabazitaxel from 2-TBS-cabazitaxel is same as Example 13.

Example 16

(100) Synthesis method of cabazitaxel from 2-TES-docetaxel is the same as Example 13.

(101) MS (m/z): 830 (M+Na). 1H NMR (CDCl.sub.3, 500 MHz): 8.12 (d, 2H), 7.63 (t, 1H), 7.51 (t, 2H), 7.327.35 (m, 5H), 6.19 (bt, 1H), 4.66 (d, 1H), 4.33 (d, 1H), 4.21 (m, 1H), 4.18 (d, 1H), 3.92 (d, 1H), 3.53 (s, 1H), 2.63 (m, 1H), 2.55 (m, 1H), 2.38 (s, 3H), 2.24 (m, 2H), 1.90 (s, 3H), 1.85 (m, 1H), 1.80 (s, 3H), 1.35 (m, 9H), 1.26 (s, 3H), 1.13 (s, 3H)

Example 17

(102) Synthesis method of 2-TES-taxol from 2-TES-7-TROC-taxol is same as Example 2.

(103) 1H NMR (CDCl3, 500 MHz): 8.12 (d, 2H), 7.73 (d, 2H), 7.51 (t, 1H), 7.44 (m, 5H), 7.38 (m, 5H), 7.03 (d, 1H), 6.24 (s, 1H), 6.22 (bt, 1H), 5.78 (dd, 1H), 5.67 (d, 1H), 4.93 (bd, 1H), 4.79 (d, 1H), 4.39 (dd, 1H), 4.30 (d, 1H), 4.19 (d, 1H), 4.11 (dd, 1H), 3.79 (d, 1H), 3.67 (bs, 1H), 2.53 (ddd, 1H), 2.43 (bs, 1H), 2.38 (s, 3H), 2.31 (dd, 1H), 2.26 (dd, 1H), 2.23 (s, 3H), 2.03 (s, 2H), 1.86 (m, 1H), 1.74 (s, 3H), 1.67 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H), 0.85 (9H, m), 0.41 (6H, m).

Example 18

(104) Synthesis method of taxol from 2-TES-taxol is the same as Example 13.

(105) MS (m/z): 876 (M+Na). 1H NMR (CDCl.sub.3, 500 MHz): 8.12 (d, 2H), 7.73 (d, 2H) 7.51 (t, 1H), 7.44 (m, 5H), 7.38 (m, 5H), 7.03 (d, 1H), 6.24 (s, 1H), 6.22 (bt, 1H), 5.78 (dd, 1H), 5.67 (d, 1H), 4.93 (bd, 1H), 4.79 (d, 1H), 4.39 (dd, 1H), 4.30 (d, 1H), 4.19 (d, 1H), 4.11 (dd, 1H), 3.79 (d, 1H), 3.67 (bs, 1H), 2.53 (dd, 1H), 2.43 (bs, 1H), 2.38 (s, 3H), 2.31 (dd, 1H), 2.26 (dd, 1H), 2.23 (s, 3H), 2.03 (s, 2H), 1.86 (m, 1H), 1.74 (s, 3H), 1.67 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H).

(106) When used in this specification and claims, the terms comprises and comprising and variations thereof mean that the specified features, steps or integers are included. The terms are not to be interpreted to exclude the presence of other features, steps or components.

(107) The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.