WO2008081247A2 - A process for the preparation of secotaxanes - Google Patents

A process for the preparation of secotaxanes Download PDF

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Publication number
WO2008081247A2
WO2008081247A2 PCT/IB2007/003951 IB2007003951W WO2008081247A2 WO 2008081247 A2 WO2008081247 A2 WO 2008081247A2 IB 2007003951 W IB2007003951 W IB 2007003951W WO 2008081247 A2 WO2008081247 A2 WO 2008081247A2
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Prior art keywords
formula
removal
branched
straight
oxazolidine
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PCT/IB2007/003951
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French (fr)
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WO2008081247A3 (en
Inventor
Gabriele Fontana
Ezio Bombardelli
Bruno Gabetta
Giovanni Appendino
Francesco Mainieri
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Indena S.P.A.
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Priority to AU2007341070A priority Critical patent/AU2007341070A1/en
Priority to CA002673238A priority patent/CA2673238A1/en
Priority to MX2009006581A priority patent/MX2009006581A/en
Priority to EP07859076A priority patent/EP2091931A2/en
Priority to JP2009542257A priority patent/JP2010513459A/en
Publication of WO2008081247A2 publication Critical patent/WO2008081247A2/en
Publication of WO2008081247A3 publication Critical patent/WO2008081247A3/en
Priority to NO20092337A priority patent/NO20092337L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention discloses a process for the preparation of secotaxanes starting from 10-deacetylbaccatin and (4S,5f?)-N-Boc-2-(2,4- dimethoxyphenyl)-4-isobutyl-1 -oxazolidine-5-carboxylic acid.
  • IDN 5390 was selected due to its anti-angiogenic properties, proved both in in vitro and in vivo studies on endothelial and ovary tumor cells. The compound proved active after oral administration on different tumor histotypes such as those of ovary, colon and breast. IDN 5390 also proved active in metastatic models and in tumors poorly sensitive to treatment with paclitaxel. A peculiarity of its action mechanism is that it is active independently from the expression state of class III beta-tubulin, a resistance mechanism to paclitaxel recently found to be important also on a clinical level (Ferlini et al., Cancer Res. 65, (6), 2397, 2005).
  • the protected secobaccatin is obtained from 10-deacetylbaccatin III by oxidation with copper acetate in methanol, followed by fragmentative reduction with hydride and protection of the 7- and 9- positions, usually with triethyl silyl chloride.
  • the resulting product is esterified with (4S,5R)-N-Boc-2- (2,4-dimethoxyphenyl)-4-isobutyl-1 -oxazolidine-5-carboxylic acid, prepared as disclosed in WO 01/02407, in the presence of a carbodiimide.
  • R1 is hydrogen or straight or branched C1-C4 alkyl, straight or branched
  • R2 is hydrogen or, together with R3, it forms a carbonate, carbamate or carbomethylene bridge;
  • R3 is hydrogen, or together with R2 it forms a carbonate, carbamate or carbomethylene bridge;
  • R4 is a straight or branched or cyclic C1-C6 aliphatic, C6-C12 aryl, or heteroaryl residue;
  • R5 is straight or branched C1-C6 alkoxy carbonyl or straight or branched C1-C6 acyl, or aryloxycarbonyl.
  • R1 , R2, R3, R4 and R5 have the meanings defined above, which process comprises the following steps: a) protection of 10-deacetylbaccatin III as the 7,10-bis-trichloroacetate; b) condensation with the derivative of formula Il or an activated analogue thereof; c) removal of the trichloroacetyls at the 7- and 10- positions; d) oxidation with copper acetate; e) removal of the oxazolidine.
  • the compounds of formula IV can be obtained from compounds of formula V
  • R6 is aryl, aryl substituted with one or more straight or branched C1-C4 alkyl or alkoxy groups
  • R7 is an alcohol-protecting group cleavable under non-acidic conditions; by means of the following steps: a) removal of the protective groups at the 7- and 10- positions; b) oxidation with copper acetate and oxygen; c) removal of the oxazolidine.
  • R1, R2, R3, R4, R5, R6, R7 have the meanings above reported
  • 10-Deacetylbaccatin III is protected at the 7- and 10- positions and condensed with compound II, obtained as disclosed in WO 01/02407.
  • the resulting coupling product is deprotected at the 7- and 10- positions and subsequently oxidized, in the presence of oxygen, with copper acetate in methanol in catalytic to stoichiometric amounts to give the product oxidized at the 10- position.
  • Said product can be isolated under kinetic conditions as a mixture of the 7-alpha and 7-beta epimers, or under thermodynamic conditions as the sole 7-alpha epimer. The problem of allyl hyper-oxidation is thereby solved, as the hydroxy group at -13 is acylated.
  • the coupling and deprotection reaction at 7,10 can be carried out in a single reactor without recovering the intermediate.
  • Deprotection of the norstatin chain of the resulting product affords the compound IDN 5910, which is also a promising taxane for the treatment of tumors.
  • fragmentative reduction and deprotection of the norstatin fragment provides IDN 5390 in high yields.
  • 10-deacetylbaccatin III is protected as the 7,10-bis- trichloroacetate as described in WO 2006/037653.
  • Groups equivalent to the trichloroacetyl groups, which can be cleaved under non-acidic conditions, e.g. carbonates such as trichloroethoxycarbonate, are also useful and preferable for this protection.
  • Condensation can be performed in a polar aprotic solvent, in the presence of N,N-4-dimethylaminopyridine.
  • Fragmentative reduction can be easily carried out by using hydrides, among which L-Selectride® is particularly preferred.
  • the trichloracetyl group is cleaved using ammonium hydroxide in a polar aprotic solvent such as acetonitrile or N-methylpyrrolidone, under the conditions indicated below, while the oxazolidine is removed using acids, such as hydrochloric acid in methanol, in either catalytic or stoichiometric amounts, under the conditions further specified in the following.
  • a polar aprotic solvent such as acetonitrile or N-methylpyrrolidone
  • the process for the preparation of IDN 5390 can be schematized as follows: a) protection of the 10-deacetylbaccatin III as the 7,10-bis- trichloroacetate
  • IDN5401 (7.2 mmols, 1.45 eqv), prepared as described in WO 01/02407, are dissolved in 40 ml of a 1 :1 toluene-water mixture. 5 ml of a 10% NaHSO4 solution in water is added thereto, monitoring that pH is about 2.5. The layers are separated, the organic one is washed with brine, dried over Na2SO4, and evaporated.
  • the intermediate is not isolated but the resulting suspension is filtered through a sintered funnel, concentrated to a volume of about 20 mL, then added with a solution of 10 ml of methanol and 2.5 ml of 25% ammonium hydroxide.
  • the mixture is stirred at room temperature, monitoring the progress by TLC (silica, petroleum ether-AcOEt 6:4; starting Rf: 0.6, final Rf: 0.3).
  • TLC sica, petroleum ether-AcOEt 6:4; starting Rf: 0.6, final Rf: 0.3.
  • the reaction is worked up by addition of 30 ml of water, acidified with H2SO4 2N, and extracted with AcOEt. The organic phase is washed with brine, dried (Na2SO- ⁇ ) and evaporated.
  • the organic phase is washed with 1 % ammonium hydroxide solution, dried over sodium sulfate and evaporated.
  • the crude can be purified by filtration on silica gel (15 g), washing with 5:5 petroleum ether-AcOEt, to obtain 2.26 g (65%) of product as an amorphous solid.
  • IR (KBr disc): 3448, 1740, 1708, 1601 , 1508, 1363, 1258, 1169, 1090, 1061 cm-'.
  • the reaction is monitored by TLC immediately after the addition of the reducing agent (silica, 6:4 petroleum ether-AcOEt; starting Rf: 0.45; final Rf: 0.30). After 15 minutes, the reaction is worked up by addition of 2N H2SO4. The organic phase is separated, further washed with brine and then evaporated. The residue is purified by gravimetric column chromatography (12.5 g of silica gel, petroleum ether- AcOEt 6:4), to obtain 613 mg of IND5570 (51 %).
  • the reducing agent sica, 6:4 petroleum ether-AcOEt; starting Rf: 0.45; final Rf: 0.30. After 15 minutes, the reaction is worked up by addition of 2N H2SO4. The organic phase is separated, further washed with brine and then evaporated. The residue is purified by gravimetric column chromatography (12.5 g of silica gel, petroleum ether- AcOEt 6:4), to obtain 613 mg of IND5570 (51 %).

Abstract

The present invention discloses a process for the preparation of secotaxanes starting from 10-deacetylbaccatin III and (4S,5R)-N-Boc-2-(2,4- dimethoxyphenyl)-4-isobutyl-1 -oxazolidine-5-carboxylic acid.

Description

A PROCESS FOR THE PREPARATION OF SECOTAXANES
The present invention discloses a process for the preparation of secotaxanes starting from 10-deacetylbaccatin and (4S,5f?)-N-Boc-2-(2,4- dimethoxyphenyl)-4-isobutyl-1 -oxazolidine-5-carboxylic acid.
BACKGROUND OF THE INVENTION
Compound IDN5390 (I), disclosed in WO 96/03394 and subsequently by Appendino et al. (Tetrahedr. Lett. 1995, 36(18), 3233-3236), is a taxane derivative presently under clinical trial as an antitumor agent.
Figure imgf000002_0001
(I) IDN 5390 was selected due to its anti-angiogenic properties, proved both in in vitro and in vivo studies on endothelial and ovary tumor cells. The compound proved active after oral administration on different tumor histotypes such as those of ovary, colon and breast. IDN 5390 also proved active in metastatic models and in tumors poorly sensitive to treatment with paclitaxel. A peculiarity of its action mechanism is that it is active independently from the expression state of class III beta-tubulin, a resistance mechanism to paclitaxel recently found to be important also on a clinical level (Ferlini et al., Cancer Res. 65, (6), 2397, 2005). IDN 5390 administered in low doses showed anti-angiogenic properties (Taraboletti et al., Anti-Cancer Drugs 14, 255, 2003). The synthetic pathway to this compound according to the prior art, as disclosed in US 5,756,776 and by Appendino et al. (Tetrahedr. Lett. 1995, 36(18), 3233-3236; Tetrahedr. Lett. 1997, 38(24), 4273-4276) usually involves esterification of a secobaccatin protected at the 7- and 9- positions as the silyl ether with the norstatine residue protected as the oxazolidine of formula (II).
Figure imgf000003_0001
(II)
The protected secobaccatin is obtained from 10-deacetylbaccatin III by oxidation with copper acetate in methanol, followed by fragmentative reduction with hydride and protection of the 7- and 9- positions, usually with triethyl silyl chloride. The resulting product is esterified with (4S,5R)-N-Boc-2- (2,4-dimethoxyphenyl)-4-isobutyl-1 -oxazolidine-5-carboxylic acid, prepared as disclosed in WO 01/02407, in the presence of a carbodiimide.
The process provides an average overall yield of 30-40%, however some drawbacks make its application on an industrial scale problematic.
First, oxidation of 10-deacetylbaccatin III with copper oxide easily causes the formation 13-oxo derivatives due to over-oxidation, thereby significantly decreasing the conversion yield. Furthermore, protection as silyl ether or ester is difficult to conduct as also the 13-position reacts, yielding useless 7,9,13-tri-protected secobaccatin.
Finally, as known to those skilled in the art, condensation of secobaccatins protected with norstatins of formula Il is more difficult than that carried out on baccatins with a whole C ring, thus requiring higher reaction temperatures and longer reaction times. The drawbacks of oxidation and protection regioselectivities, as well as the difficulty to perform condensation with chains of formula II, induced the Applicant to develop a novel semi-synthetic approach which is the object of the invention.
DISCLOSURE OF THE INVENTION
It has now been found that the above described synthetic problems can be solved by the following synthetic scheme, that can be advantageously applied not only to the above compound of formula (I) but generally to the class of taxane compounds of formula (III)
Figure imgf000004_0001
wherein
R1 is hydrogen or straight or branched C1-C4 alkyl, straight or branched
C1-C4 alkoxy, F, Cl, Br, I;
R2 is hydrogen or, together with R3, it forms a carbonate, carbamate or carbomethylene bridge;
R3 is hydrogen, or together with R2 it forms a carbonate, carbamate or carbomethylene bridge; R4 is a straight or branched or cyclic C1-C6 aliphatic, C6-C12 aryl, or heteroaryl residue; R5 is straight or branched C1-C6 alkoxy carbonyl or straight or branched C1-C6 acyl, or aryloxycarbonyl. Compounds of formula III are prepared according to the invention with a process comprising the following steps: a) protection of 10-deacetylbaccatin III as the 7,10-bis-trichloroacetate; b) condensation with the derivative of formula Il or an activated analogue thereof; c) removal of the trichloroacetyls at the 7- and 10- positions; d) oxidation with copper acetate; e) fragmentative reduction; f) removal of the oxazolidine. The invention, in a further aspect, also provides a process for the preparation of compounds of formula IV
Figure imgf000005_0001
(IV) wherein
R1 , R2, R3, R4 and R5 have the meanings defined above, which process comprises the following steps: a) protection of 10-deacetylbaccatin III as the 7,10-bis-trichloroacetate; b) condensation with the derivative of formula Il or an activated analogue thereof; c) removal of the trichloroacetyls at the 7- and 10- positions; d) oxidation with copper acetate; e) removal of the oxazolidine. The compounds of formula IV can be obtained from compounds of formula V
Figure imgf000006_0001
(V) wherein R1 , R2, R3, R4 and R5 have the meanings defined above;
R6 is aryl, aryl substituted with one or more straight or branched C1-C4 alkyl or alkoxy groups; R7 is an alcohol-protecting group cleavable under non-acidic conditions; by means of the following steps: a) removal of the protective groups at the 7- and 10- positions; b) oxidation with copper acetate and oxygen; c) removal of the oxazolidine.
The following intermediates are novel and are a further object of the invention:
Figure imgf000006_0002
Figure imgf000007_0001
wherein R1, R2, R3, R4, R5, R6, R7 have the meanings above reported,
Figure imgf000007_0002
DETAILED DISCLOSURE OF THE INVENTION
10-Deacetylbaccatin III is protected at the 7- and 10- positions and condensed with compound II, obtained as disclosed in WO 01/02407. The resulting coupling product is deprotected at the 7- and 10- positions and subsequently oxidized, in the presence of oxygen, with copper acetate in methanol in catalytic to stoichiometric amounts to give the product oxidized at the 10- position. Said product can be isolated under kinetic conditions as a mixture of the 7-alpha and 7-beta epimers, or under thermodynamic conditions as the sole 7-alpha epimer. The problem of allyl hyper-oxidation is thereby solved, as the hydroxy group at -13 is acylated.
The coupling and deprotection reaction at 7,10 can be carried out in a single reactor without recovering the intermediate. Deprotection of the norstatin chain of the resulting product affords the compound IDN 5910, which is also a promising taxane for the treatment of tumors. Alternatively, fragmentative reduction and deprotection of the norstatin fragment provides IDN 5390 in high yields. Preferably, 10-deacetylbaccatin III is protected as the 7,10-bis- trichloroacetate as described in WO 2006/037653. Groups equivalent to the trichloroacetyl groups, which can be cleaved under non-acidic conditions, e.g. carbonates such as trichloroethoxycarbonate, are also useful and preferable for this protection. Condensation can be performed in a polar aprotic solvent, in the presence of N,N-4-dimethylaminopyridine.
Fragmentative reduction can be easily carried out by using hydrides, among which L-Selectride® is particularly preferred.
The trichloracetyl group is cleaved using ammonium hydroxide in a polar aprotic solvent such as acetonitrile or N-methylpyrrolidone, under the conditions indicated below, while the oxazolidine is removed using acids, such as hydrochloric acid in methanol, in either catalytic or stoichiometric amounts, under the conditions further specified in the following.
More particularly, the process for the preparation of compound IDN 5910 can be schematized as follows:
a) protection of 10-deacetylbaccatin III as the 7,10-bis-trichloroacetate
Figure imgf000009_0001
b) condensation with the derivative of formula Il or an activated analogue thereof
Figure imgf000009_0002
c) removal of the trichloroacetyls at the 7- and 10- positions
Figure imgf000009_0003
d) oxidation with copper acetate
Figure imgf000010_0001
e) removal of the oxazolidine
Figure imgf000010_0002
The process for the preparation of IDN 5390 can be schematized as follows: a) protection of the 10-deacetylbaccatin III as the 7,10-bis- trichloroacetate
Figure imgf000010_0003
b) condensation with the derivative of formula Il or an activated analogue thereof
Figure imgf000011_0001
c) removal of the trichloroacetyls at the 7- and 10- positions d) oxidation with copper acetate
Figure imgf000011_0002
Figure imgf000011_0003
e) fragmentative reduction
Figure imgf000012_0001
f) removal of the oxazolidine
Figure imgf000012_0002
The processes described above have general validity in that the reaction mechanisms and sequences do not depend on any substituents or other functional groups present on the molecules.
The following examples illustrate the invention in further detail. [EXAMPLE 1 - Preparation of 10-deacetylbaccatin III 7,10-bis- trichloroacetate
15 g of 10-deacetylbaccatin III is dissolved in 60 ml of pyridine, with stirring and dry conditions. The solution is cooled to 0-50C, and 6.3 ml of trichloroacetyl chloride is dropped therein. The reaction mixture is stirred at
O0C until disappearance of the starting material (about 1 hour). Then dichloromethane (100 ml_) and 4N hydrochloric acid (100 ml_) are added keeping temperature below 1O0C. The two phases are then separated and the organic phase is extracted again with 4N HCI (100 ml_). The organic phase is washed with brine (50 ml_) and concentrated under vacuum. The residue is taken up into toluene (100 ml_). The suspension is stirred for 2 hours and the precipitate collected on the filter and washed with 15 ml of toluene. 24 grams of wet product are obtained (83% HPLC titre as such, HPLC purity 93.3%). The product can be either used directly for the subsequent reaction or further purified by column chromatography.
1H NMR (300 MHz, CDCI3, J in Hz, 30(C) 8.16 (m.Bz), 7.67 (m.Bz), 7.54 (m.Bz), 6.54 (s,10), 5.77 (dd,10.5; 7.4, H-7), 5.74 (d, 6.9, H-2), 5.03 (dd, 9.6; 1.6, H-5), 4.96 (td, 8.5; 1.2, H-13), 4.40 (d, 8.4, H-20a), 4.22 (dd, 8.3, 0.6, H-20b), 4.06 (d, 6.9, H-3), 2.75 (ddd, 14.5; 9.6; 7.4, H-6a), 2.07 (ddd, 14.4; 10.4; 1.8, H-6b), 2.38 (d, 8.4, H-14), 2.36 (s, 4-OAc), 2.26 (d, 1.4, H-18), 1.95 (s, H-19), 1.23 (s, H-17), 1.15 (s, H-16).
13C NMR (75 MHz, CDCI3, 30(C) 199.9 (s, 9), 171.1 (s, 4-OCOMe), 167.2 (s, 2-OCOPh), 162.2 (s, 7-OCOCCI3), 161.0 (s, 10-OCOCCI3), 147.7 (s, C-12), 134.1 (d, Bz), 130.7 (d, Bz), 130.4 (s, C-11), 129.4 (s, Bz), 129.0 (d, Bz), 83.7 (d, C-5), 80.4 (s, C-4), 79.5 (d, C-10), 79.4 (s, C-1), 76.5 (d, C-7), 74.4 (d, C-2), 76.8 (t, C-20), 68.0 (d, C-13), 56.8 (s, C-8), 47.3 (d, C-3), 42.9 (s, C-15), 38.7 (t, C-14), 32.7 (t, C-6), 26.7 (q, C-16), 22.7 (q, 4-OCOCH3), 20.3 (q, C-17), 15.7 (q, C-18), 10.9 (q, C-19). (EXAMPLE 2 - Condensation of 7,10-bis-trichloroacetyl
10-deacetylbaccatin III with (4S,5R)-N-BOC-2-(2,4-dimethoxyphenyl)-4- isobutyl-1,3-oxazolidine-5-carboxylic acid and subsequent cleavage of trichloroacetyls groups
2.9 grams of IDN5401 (7.2 mmols, 1.45 eqv), prepared as described in WO 01/02407, are dissolved in 40 ml of a 1 :1 toluene-water mixture. 5 ml of a 10% NaHSO4 solution in water is added thereto, monitoring that pH is about 2.5. The layers are separated, the organic one is washed with brine, dried over Na2SO4, and evaporated. The residue is taken up in 10 ml of dry toluene cooled at 00C is dropped into a solution of 3.70 g of the intermediate from Example 1 (4.4 mmols) in 20 ml of toluene, 660 mg of solid DMAP (5.4 mmols, 1.17 equiv.) and 751 mg of dicyclohexyl carbodiimide (1.77 equiv; 8.2 mmols). The reaction is stirred at 00C for 30 minutes, then for 1 hour at room temperature, monitoring the progress by TLC (silica, petroleum ether-AcOEt 7:3, starting Rf: 0.25; final Rf: 0.45). After 2 hours the reaction is completed. The suspension is filtered through a sintered funnel. The intermediate can be obtained by evaporation of the solvent and column chromatography of the residue (7:3 petroleum ether-ethyl acetate as the eluent). 1H NMR (300 MHz, CDCI3): δ 8.05 (2H, d, J = 7.4 Hz, or-Bz), 7.61 (1 H, t, J = 7.4 Hz, P-Bz), 7.46 (2H, t, J = 7.4 Hz, m-Bz), 7.22 (1 H, d, J = 8.5 Hz, Ar-6), 6.59 (1 H, s, Ar-C(N)(OR)H), 6.50 (2H, br s, Ar-3 + Ar-5), 6.48 (1 H, s, H-10), 6.24 (1 H, t, J = 8.5 Hz, H-13), 5.76 (2H, m, H-7 + H-2), 4.94 (1 H, d, J = 9.8 Hz, H-5), 4.51 (2H, m, H-21 + H-31), 4.34 (1 H, d, J = 8.3 Hz, H-20a), 4.16 (1 H, d, J = 8.3 Hz, H-20b), 4.00 (1 H, d, J = 8.8 Hz, H-3), 3.88 (3H, s, OMe), 3.86 (3H, s, OMe), 2.29 (3H, br s, H-18), 1.90 (3H, s, H-19), 1.19, 1.17 (2 x 3H, s, H-16 + H-17), 1.07 (6H, m, H-61 + H-71).
Preferably, the intermediate is not isolated but the resulting suspension is filtered through a sintered funnel, concentrated to a volume of about 20 mL, then added with a solution of 10 ml of methanol and 2.5 ml of 25% ammonium hydroxide. The mixture is stirred at room temperature, monitoring the progress by TLC (silica, petroleum ether-AcOEt 6:4; starting Rf: 0.6, final Rf: 0.3). After 2 hours, the reaction is worked up by addition of 30 ml of water, acidified with H2SO4 2N, and extracted with AcOEt. The organic phase is washed with brine, dried (Na2SO-ι) and evaporated. The residue is purified by gravimetric column chromatography (35 g of silica gel, 6:4 petroleum ether-AcOEt as the eluent), to obtain 2.67 g of product (65%). 1H NMR (300 MHz, CDCI3): δ 8.03 (2H, d, J = 7.4 Hz, or-Bz), 7.58 (1H, br t, J = 7.4 Hz, p-Bz), 7.45 (2H, d, J = 8.5 Hz, m-Bz), 7.21 (1 H, d, J = 8.5 Hz, Ar-6), 6.59 (1 H, s, Ar-C(N)(OR)H)), 6.47 (2H, m, Ar-3 + Ar-5), 6.17 (1 H, t, J = 8.4 Hz, H-13), 5.66 (1 H, d, J = 9.3 Hz, H-2), 5.24 (1 H, s, H-10), 4.93 (1 H, d, J = 9.6 Hz, H-5), 4.45 (2H, m, H-21 + H-71), 4.28 (1 H, d, J = 8.1 Hz, H-20a), ca. 4.28 (1 H, m, H-3'), 4.16 (1 H, d, J = 8.1 Hz, H-20b), 3.95 (1 H, d, J = 7.3 Hz, H-3), 3.86 (3H, OMe), 3.81 (3H, s, OMe), 2.26 (3H, br s, H-18), 2.12 (3H, s, OAc), 1.71 (3H, s, H-19), 1.23 (9H, s, N-BOC), 1.20 (3H, s, H-16(17)), 1.10 (3H, s, H-17(16)), 1.06 (6H, d, J = 6.0 Hz, H-6' + H-71).
EΞXAMPLE 3 - Oxidation with copper acetate and oxygen 2.0 g of intermediate from Example 2 (2.1 mmols) is dissolved in 20 ml of a 1 :1 methanol and DMF mixture. Afterwards, 200 mg of Cu(OAc)2.3H2θ is added with strong stirring. The reaction is stirred, bubbling nitrogen containing 5% oxygen. The progress is monitored by TLC (starting Rf: 0.25; final Rf: 0.45). After completion of the reaction, the mixture is filtered through Celite, and methanol is distilled off under vacuum. The residue is poured in water and extracted with ethyl acetate (25 ml_). The organic phase is washed with 1 % ammonium hydroxide solution, dried over sodium sulfate and evaporated. The crude can be purified by filtration on silica gel (15 g), washing with 5:5 petroleum ether-AcOEt, to obtain 2.26 g (65%) of product as an amorphous solid.
1H NMR (200 MHz, CDCI3): δ 8.08 (d, J = 7.4 Hz, AA'-Bz), 7.62 (t, J = 7.4 Hz, C-Bz)1 7.48 (t. J = 7.4 Hz, BB'-Bz), 7.15 (d, J = 8.1 Hz, H-181), 6.59 (br s, H-71), 6.51 (br d, J = 8.1 Hz, H- 17'), 6.45 (br s, H-15'), 6.17 (br t, J = 8.4 Hz, H-13), 5.87 (d, J = 9.0 Hz, H-2), 4.91 (t, J = 7.5 Hz, H-7), 4.72 (br d, J =10 Hz, H-5), ca.4.55 (m, H-21 and H-3'), 4.40 (d, J = 8.0 Hz1 H-20a), 4.31 (d, J = 8.0 Hz, H-20 b), 4.07 (br s, H-7), 3.80 (s, OMe), 2.46 (dd, J = 16.0 and 10.0 Hz, H-6a), 2.36 (br s, 18-Me)12.08 (s, 4-OAc), 1.96 (s, 19-Me)11.38 (s, BOC), 1.28 and 1.21 (s, H-16 and H-17), 1.09 (d, H-61). 13C NMR (50 MHz, CDCI3): δ 207.9, 188.5, 172.4, 171.1 , 171.1 , 167.0, 161.5, 159.1 , 152.9, 142.9, 141.2, 133.9, 130.0, 129.1 , 128.7, 104.3, 96.3, 82.6, 81.3, 80.7, 79.8, 79.5, 76.6, 75.1 , 71.2, 58.9, 57.1 , 55.4, 43.6, 40.2, 39.6, 36.5, 35.2, 28.1 , 27.0. 26.1 , 25.7, 23.1 , 22.6, 21.9, 21.8, 15.0, 14.4. (EXAMPLE 4 - Cleavage of the oxazolidine to give IDN 5910
The solution of the product from Example 3 (1 g, 1.07 mmols) in methanol (15 mL) is added with trifluoroacetic acid (0.060 mL) and the mixture is stirred for 8 hours at room temperature. Then dichloromethane (15 mL) and water (20 mL) are added. The phases are separated. The aqueous phase is extracted with dichloromethane (10 mL). The combined organic phases are washed with water (10 mL) and dried over Na2SO-t. The solvent is evaporated off and the crude is purified by column chromatography (silica,
40 g, 70:30 petroleum ether - ethyl acetate). The fractions containing IDN
5910 are combined and the solvent is evaporated off thus affording 680 mg (72%) of product as a white solid.
1H NMR (300 MHz, CDCI3, J in Hz, 25(C) 8.13 (d, J = 8.3, Bz), 7.62 (t, J = 8.3, Bz), 7.54 (t, J = 8.3, Bz), 6.15 (br t, J = 9.0, H-13), 5.84 (d, J = 7.2, H-2), 4.90 (br t, J = 5.4, H-31), 4.64 (d, J = 10.0, H-5), 4.45 (br s, H-21), 4.41 (d, J = 8.8, H-20a), 4.32 (d, J = 8.8, H-20b), 4.18 (br s, H-7), 4.01 (d, J = 7.2, H-3), 2.48 (s, 4-Ac), 1.80 (br s, H-18), 1.72 (s, H-19), 1.24 (s, H-15), 1.21 (s, H-16), 0.97 (d, J = 6.8, H-61), 0.95 (d, J = 6.8, H-71).
IR (KBr disc): 3448, 1740, 1708, 1601 , 1508, 1363, 1258, 1169, 1090, 1061 cm-'.
13C NMR (75 MHz, CDCI3, RT) 207.9 (s), 188.6 (s), 172.5 (s), 172.0 (S), 166.9 (s), 155.7 (s), 143.3 (s), 141.0 (s), 133.8 (d), 130.2 (d), 129.2 (s),
128.7 (d), 82.6 (d), 81.6 (s), 79.8 (s), 79.1 (s), 77.4 (t), 77.1 (d), 75.0 (d),
73.0 (d), 71.9 (d), 57.1 (s), 51.4 (d), 41.0 (t), 40.2 (s), 39.4 (d), 36.0 (t), 35.2
(t), 30.8 (d), 28.1 (q), 25.9 (q), 24.7 (q), 23.1 (q), 22.6 (q), 22.3 (q), 21.9 (q), 14.9 (q), 14.2 (q).
[EXAMPLE 5 - Fragmentative reduction
A cooled solution (-150C, ice bath) of 10-deacetyl-10-dehydro-13- baccatinyl (4S,5R)-Λ/-BOC-2-(2,4-dimethoxyphenyl)-4-isobutyI-1 ,3-oxa- zolidine-5-carboxylate (1 ,20 g, 1 ,28 mmols) in anhydrous THF (10 mL), is added drop by drop with a 1.0 M solution of L-Selectride in THF (3.00 mL, 3.00 mmols, 2.3 equiv). The reaction is monitored by TLC immediately after the addition of the reducing agent (silica, 6:4 petroleum ether-AcOEt; starting Rf: 0.45; final Rf: 0.30). After 15 minutes, the reaction is worked up by addition of 2N H2SO4. The organic phase is separated, further washed with brine and then evaporated. The residue is purified by gravimetric column chromatography (12.5 g of silica gel, petroleum ether- AcOEt 6:4), to obtain 613 mg of IND5570 (51 %).
1H NMR (300 MHz, CDCI3, J values in Hz, 30(C) 8.03 (d, 7.4, m-Bz), 7.65 (t, 7.4, p-Bz), 7.52 (t, 7.4, or-Bz), 7.22 (d, 8.6, H-181), 6.62 (s, H-71), 6.56 (s, H-9-OH), 6.52 (dd, 8.6, 2.5, H-171) 6.48 (d, 2.3, H-151), 6.17 (td, 8.4, 1.4, H-13), 5.68 (d, 9.4, H-2), 4.67 (m, H-21), 4.56 (dd, 8.3, 4.5, H-31), 5.23 (d, 11.2, H-5), 4.35 (s-broad, H-3), 5.31 (s-broad, H-20), 4.32 (d, 7.8), 3.84 (s, OMe), 3.84 (s, OMe), 3.85 (m, H-7), 3.49 (m), 2.76 (m, H-14), 2.62 (dd, 16.3, 9.7), 2.08 (d, 1.2, H-18), 1.85 (s-broad, H-41), 1.69 (m), 1.93 (s-broad, H-19), 2.16 (m, H-6), 1.86 (m, H-51), 1.86 (s, OCOCH3), 1.31 (s, H-17), 1.16 (s, H-16), 1.10 (d, 6.2, H-61), 1.10 (d, 6.1 , H-61), 1.36 (t-But), 8.45 (s, 9-OH), 8.02 (d, 7.2, m-Bz), 7.69 (t, 7.2, p-Bz), 7.53 (t, 7.2, or-Bz), 7.15 (d, 8.1 , H-181), 6.58 (m, H-171), 6.58 (m, H-151), 6.45 (s, H-71), 6.06 (t, 8.0, H-13), 5.53 (d, 9.2, H-2), 5.05 (OH), 4.82 (s-broad, H-5), 4.44 (t 4.6, H-31), 4.14 (m, H-20), 3.80 (s, 16'-OMe), 3.77 (s, 14'-OMe), 3.64 (m, H-7), 3.26 (m), 2.48 (dd, 15.7, 9.0, H-14), 1.89 (s-broad, H-18), 1.85 (m, H-51), 1.81 (s-broad, H-16), 1.69 (m, H-41), 1.27 (s-broad, t-But), 1.10 (d, 6.6, H-6'), 1.05 (d, 6.6, H-61), 1.86 (s, OCOCH3).
13C NMR (75 MHz, CDCI3, 300C) 191.4 (s, 10), 171.2 (s, C-11 + OCOCH3), 169.3 (s, C-101), 167.7 (s, COBz), 161.9 (s, C-161), 159.2 (s, C-141), 153.2 (s, C-131), 149.1 (s, C-9), 142.7 (s, C-11), 136.6 (s, C-12), 134.1 (d, p-Bz), 129.5 (s, q-Bz), 129.8 (d, m-Bz), 129.2 (d, or-Bz), 127.8 (d, C-18'), 125.0 (s, C-8), 104.8 (d, C-171), 98.6 (d, C-151), 87.3 (d, C-71), 86.4 (s, C-4), 86.4 (d, C-5), 80.7 s,8'), 81.0 (s, C-1), 80.3 (d, C-21), 74.9 (d, C-2), 75.0 (t, C-20), 71.0 (d, C-13), 59.2 (d, C-31), 59.7 (t, C-7), 55.8 (q, OMe), 55.6 (q, OMe), 44.9 (d, C-3),), 43.8 (t, C-41), 43.2 (s, C-15), 37.1 (t, C-14), 38.5 (t, C-6), 28.4 (q, t-But), 25.9 (q, C-17), 22.4 (q, OCOCH3), 25.2 (d, C-51), 23.4 (q, C-61), 22.3 (q, C-61), 21.2 (q, C-16), 15.2 (q, C-18), 14.7 (q, C-19). EXAMPLE 6 - Cleavage of the oxazolidine to give IDN 5390 Trifluoroacetic acid (0.2 ml_) is added to a solution of the product from Example 5 (4 g, 2.7 mmols) in methanol (12 ml_) and the mixture is stirred overnight at room temperature. Then dichloromethane (20 mL) and water (14 ml_) are added and the phases are separated. The aqueous phase is extracted with further dichloromethane (5 mL). The combined organic phases are washed with water (2 mL) and dried over sodium sulfate. The organic phase is subjected to column chromatography (60 g silica packed with dichloromethane) and eluted first with dichloromethane then with CH2Cl2:95%EtOH = 98:2. The fractions containing the desired product are combined, the solvent is evaporated off under reduced pressure and the residue is dissolved in THF (10 mL). This solution is added with n-heptane (10 mL) under stirring and left to stand for 2 hours. The crystallized product is filtered and dried under vacuum at 600C. Yield 1.53 g (1.94 mmols, 71%) of IDN 5390.
1H-NMR: (CDCI3, 300 MHz): 8.09 (d, 7.4, or-Bz), 7.63 (t, 7.5, p-Bz), 7.50 (t, 7.5, m-Bz), 6.46 (s, 9-OH), 6.25 (dt, 8.8, 1.2, H13), 5.65 (d, 9.6, 2H), 5.29 (d, 11.6, H5), 5.18 (m, 20a), 4.72 (d, 10.0, NH), 4.39 (d, 9.0, H3), 4.34 (d, 9.0, 20 b), 4.27 (d, 2.8, H2"), 4.21 (m, H31), 3.92 (m, 7a), 3.75 (dd, 11.0, 6.1 , 7b), 2.86 (m, 14a), 2.50 (m, 6a), 2.49 (dd, 15.6, 9.8, 14b), 2.14 (s, H16), 2.12 (m, H6b), 1.94 (s, 4-OAc)1 1.92 (d, 1.5, H18), 1.90 (s, H19), 1.73 (m, H51), 1.63 (m, H4'a), 1.46 (m, 4'b), 1.33 (s, Boc), 1.29 (s, H17), 1.03 (d, 6.6, H6'), 1.02 (d, 6.6, H71).

Claims

1. A process for the preparation of compounds of formula
Figure imgf000020_0001
(III) wherein
R1 is hydrogen or straight or branched C1-C4 alkyl, straight or branched
C1-C4 alkoxy, F, Cl, Br, I; R2 is hydrogen or, together with R3, it forms a carbonate, carbamate or carbomethylene bridge; R3 is hydrogen, or together with R2 it forms a carbonate, carbamate or carbomethylene bridge; R4 is a straight or branched or cyclic C1-C6 aliphatic, C6-C12 aryl, or heteroaryl residue;
R5 is straight or branched C1-C6 alkoxy carbonyl or straight or branched C1-C6 acyl, or aryloxycarbonyl.
Which process comprises steps: a) protection of 10-deacetylbaccatin III as the 7,10-bis-trichloroacetate; b) condensation with the derivative of formula Il or an activated analogue thereof; c) removal of the trichloroacetyls at the 7- and 10- positions; d) oxidation with copper acetate; e) fragmentative reduction; f) removal of the oxazolidine.
2. A process for the preparation of compounds of formula IV
Figure imgf000021_0001
(IV) wherein R1 , R2, R3, R4 and R5 have the meanings defined above, which process comprises the following steps: a) protection of 10-deacetylbaccatin III as the 7,10-bis-trichloroacetate; b) condensation with the derivative of formula Il or an activated analogue thereof; c) removal of the trichloroacetyls at the 7- and 10- positions; d) oxidation with copper acetate; e) removal of the oxazolidine.
3. A process for the preparation of compounds of formula IV from compounds of formula V
Figure imgf000021_0002
(V) wherein R1 , R2, R3, R4 and R5 have the meanings defined above;
R6 is aryl, aryl substituted with one or more straight or branched C1-C4 alkyl or alkoxy groups; R7 is an alcohol-protecting group cleavable under non-acidic conditions; by means of the following steps: a) removal of the protective groups at the 7- and 10- positions; b) oxidation with copper acetate and oxygen; c) removal of the oxazolidine.
4. A compound selected from
Figure imgf000022_0001
or
Figure imgf000022_0002
wherein R1 , R2, R3, R4, R5, R6, R7 have the meanings above reported, or
Figure imgf000023_0001
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