Methods for preparing taxane derivatives

Abstract

A method for preparing taxane derivatives is provided. [Solution] Disclosed is a method for preparing a taxane esterified with octadecanedioic acid, the method comprising reacting the taxane with octadecanedioic acid, one of whose two carboxyl groups is protected with a group removable by transition metal catalysis.

Description

[Technical field]

[0001] The present invention relates to a method for preparing high purity taxane derivatives. [Background technology]

[0002] Taxanes are a class of antitumor agents widely used in chemotherapy, stabilizing microtubule polymerization at the cellular level and thereby inhibiting mitosis. The compounds can be obtained, for example, from the bark of Taxus brevifolia by extraction and purification, or by a semisynthetic process starting from 10-deacetylbaccatin of formula (1). The most widely used taxane anticancer agent in clinical practice is paclitaxel ("PTX") of formula (2), which is used to treat lung cancer, ovarian cancer, breast cancer, head and neck cancer, and advanced Kaposi's sarcoma. Docetaxel of formula (3) is used to treat operable breast cancer, non-small cell lung cancer, prostate cancer, and gastric adenocarcinoma. Cabazetaxel of formula (4) is used to treat inoperable ptomas of the prostate. Although these antitumor agents are widely used, their use is accompanied by many side effects, some of which are severe.

[0003] [ka]

[0004] [ka]

[0005] [ka]

[0006] [ka] Summary of the Invention [Problem to be solved by the invention]

[0007] ODDA-paclitaxel ("ODDA-PTX") of formula (5) is a prodrug of paclitaxel (2); the compound, after esterification with octadecanedioic acid ("ODDA") of formula (6), promotes non-covalent binding between paclitaxel (2) and human serum albumin, thereby reducing side effects due to damage to healthy tissues, and is preferably taken up by some tumor cells that overexpress certain surface proteins, such as the protein CD36, which promotes the transport of fatty acids into cells (WO2021 / 007322).

[0008] [ka]

[0009] The properties of ODDA-paclitaxel (5) have been validated by in vivo studies and demonstrated to be more effective than conventional formulations of paclitaxel (2) in the treatment of fibrosarcoma, pancreatic cancer, and colon cancer (Callmann et al., J. Am. Chem. Soc. 2019, 141, 11765-11769).

[0010] Callmann et al. describe a method for the preparation of ODDA-paclitaxel (5) by esterification of octadecanedioic acid (6) and paclitaxel of formula (2) in the presence of a condensing agent such as ethyl-dimethylaminopropyl-carbodiimide ("EDC") and dimethylaminopyridine ("DMAP").

[0011] [ka]

[0012] [ka]

[0013] However, the above synthetic approach can provide ODDA-paclitaxel (5) in only low yields due to esterification of the paclitaxel hydroxyls (2) present at the 2' and 7 positions due to the formation of by-products such as fused paclitaxel-ODDA-paclitaxel ("PTX-ODDA-PTX") of formula (7) and ODDA-paclitaxel-ODDA ("ODDA-PTX-ODDA") of formula (8).

[0014] [ka]

[0015] [ka]

[0016] An alternative synthetic method exemplified in WO2017 / 053391 and WO2021 / 007322 involves initial conversion of ODDA (6) to the mono-triisopropylsilyl ester of formula (9).

[0017] [ka] Paclitaxel (2) is then esterified with a compound of formula (9) to give a compound of formula (10).

[0018] [ka] Finally, the silicon protecting groups are removed to give ODDA-paclitaxel (5).

[0019] [ka]

[0020] The synthesis method prevents the formation of the impurity PTX-ODDA-PTX (7) by using compound (9), but does not prevent the formation of ODDA-PTX-ODDA (8).

[0021] Furthermore, the presence of impurities in commercially available ODDA, such as diacids with chains of more or less carbon atoms, can lead to the formation of further undesirable derivatives.Therefore, there is a need to develop methods to provide ODDA-PTX (5), and possibly other ODDA-taxanes, in high purity. [Means for solving the problem]

[0022] The applicant has developed a novel method for preparing ODDA-taxanes of general formula (11).

[0023] [ka]

[0024] where R1, R3, R4, R8 and R9 are identical or different and are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl, which in turn may be substituted or alternated with one or more groups G, which may be identical or different from one another, where G=-OH, -SH, -NH2, halogen, -CN, -NO2, -OR 12 , -SR 12 , -NHR 12 , -NR 12 R 13 >C=O, >C=S, >C=NH, >C=NR 12 , -C(O)R 12 , -C(O)HC(O)OH.-C(O)NH2, -C(O)Halogen, -C(O)OR 12 , -C(O)SR 12 , -C(O)NHR 12 , -C(O)NR 12 R 13 , -OC(O)OR 12 , -OC(O)NHR 12 , -NHC(O)NHR 12 or -NHC(S)NHR 12 It is. R2, R6, R7, R 10 and R11 are the same or different and are H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, -OH, -SH, -NH 2、 -NH- or -N<, which in turn may be substituted by one or more groups G', which may be identical or different, or may be alternately substituted with one or more groups G', where G'=-OH, -SH, -NH2, halogen, -CN, -NO2, -OR 12 , -SR 12 , -NHR 12 , -NR 12 R 13 >C=O, >C=S, >C=NH, >C=NR 12 , -C(O)R 12 , -C(O)HC(O)OH, -C(O)NH2, -C(O)Halogen, -C(O)OR 12 , -C(O)SR 12 , -C(O)NHR 12 , -C(O)NR 12 R 13 , -OC(O)OR 12 , -OC(O)NHR 12 , -NHC(O)NHR 12 or -NHC(S)NHR 12 and; R5 = H, alkyl, alkenyl or cycloalkyl. R 12 and R 13 are the same or different and are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl, which in turn may be substituted by one or more groups X which are the same or different from each other, or may be substituted alternately with one or more groups X, where X=-CH3, -CH2-, -CH<, -OH, -SH, -NH2, halogen, -CN, -NO2, -O-, -S-, -NH-, -N<, >C=O, >C=S, >C=NH, >C=N-, -C(O)HC(O)OH, -C(O)NH2, -C(O)halogen, -C(O)O-, -C(O)S-, -C(O)NH-, -C(O)N<, -OC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(S)NH-. R2 and R5 together may form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted with one or more groups G or alternatingly substituted with one or more groups G, where G is as defined above. R6 and R7 together may form a group =Y, where Y =CH2, =O, =S, =NH, =N-. R1 and R6 together may form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted or alternating with one or more identical or different groups G, where G is as defined above. R8 and R 10 may be taken together to form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted or alternating with one or more identical or different groups G, where G is as defined above.

[0025] [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The term "alkyl" refers to a straight or branched C1-C 20 The term "alkenyl" defines a straight or branched C2-C alkyl group containing at least one carbon-carbon double bond. 20 The term "alkynyl" defines a straight or branched C2-C alkyl group containing at least one carbon-carbon triple bond. 20 The term "aryl" defines a cyclic or polycyclic C3-C 20 Defines an aromatic system, the term "heteroaryl" refers to a cyclic or polycyclic C3-C heterocyclic ring system containing at least one N, O or S atom. 20 Define aromatic system.

[0027] For clarity, the term "taxane" defines a compound containing the skeleton of formula (13).

[0028] [ka]

[0029] The process according to the invention provides a compound of formula (11) in high purity, where "high purity" means the presence of impurities of formulae (12a) and (12b) in amounts less than those reported in the prior art; preferably the amount of impurities as measured by HPLC analysis does not exceed 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%; more preferably the absence of impurities of formulae (12a) and (12b). Said compound constitutes a further aspect of the invention. The formation of said impurity is due to the presence of compound of formula (6a) in compound of formula (6).

[0030] [ka]

[0031] In particular, the method provides a compound of formula (5) containing no more than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of an impurity of formula (8) as determined by HPLC analysis, and preferably provides a compound of formula (5) free of the impurity of formula (8), which compound is a further aspect of the invention.

[0032] In its first aspect, the present invention relates to a process for preparing a compound of formula (11), comprising the steps of: a) reacting a compound of formula (14) with

[0033] [ka] Here, R1 to R 13 is defined as above; reacting with a compound of formula (15),

[0034] [ka] Here, R 14 is a protecting group that can be removed by catalytic reaction with a transition metal b) Removal of the protecting group.

[0035] A compound of formula (14) is preferably used.

[0036] [ka]

[0037] where R1, R3, R4, R8 and R9 are the same or different; H, C1 to C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl and C3-C 10 heteroaryl, optionally substituted or alternating with one or more groups G which may be identical or different, where G is as defined above. R2, R6, R7, R 10 and R 11 are the same or different, H, C1 to C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C3-C 10 Heteroaryl, -OH, -SH, -NH2, -NH- and -N<, optionally substituted by one or more groups G' which are the same or different, or alternately substituted with one or more groups G', where G' is as defined above. R5 = H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl or C3-C6 cycloalkyl. R2 and R5 together may form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted by one or more groups G or alternating with one or more groups G, where G is as defined above. R6 and R7 together may form a group =Y, where Y =CH2, O, S, NH or N-. R1 and R6 together may form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted by one or more groups G or alternating with one or more groups G, where G is as defined above; More preferably, the compound of formula (14) is selected from paclitaxel (2), docetaxel (3), cabazitaxel (4), larotaxel (16), ortataxel (17), BMS-184476 (18), tesetaxel (19), mirataxel (20), SB-T-1214 (21), SB-T-1216 (22), SB-T-121602 (23), SB-T-12854 (24) and docetaxel-f3-t-Boc (25). more preferably, they are selected from paclitaxel (2), docetaxel (3), ortataxel (17), tesetaxel (19), SB-T-1214 (21), SB-T-1216 (22), SB-T-121602 (23), SB-T-12854 (24) and docetaxel-f3-t-Boc (25); even more preferably, they are selected from paclitaxel (2) and docetaxel (3).

[0038] [Table 1] The compound of formula (15) is preferably used

[0039] [ka] Here, R 14 is allyl or 1,1-dimethyl-2-butenyl; more preferably, a compound of formula (15) is used

[0040] [ka] Here, R 14 is an allyl.

[0041] Compounds of formula (15), in particular R 14 The compounds in which is allyl represent a second aspect of the invention.

[0042] Typically, R 14 The compound of formula (15) having allyl group is characterized as follows:

[0043] The XRPD spectrum shows a crystalline structure and contains characteristic reflections at angles of 2θ° with relative intensities of greater than 5% and approximately 4.95; 8.27; 21.33 (±0.2). In particular, the XRPD spectrum of the compound of formula (15) shows a crystalline structure and contains characteristic reflections at angles of 2θ° with relative intensities of greater than 1% and approximately corresponding to 3.22, 4.95, 6.60, 8.27, 11.61, 13.29, 20.02, 20.75, 21.33, 21.97, 23.41, 24.23, 37.21, 38.98, 40.75 (±0.2). More particularly, the XRPD spectrum of compound of formula (15) shows a crystalline structure with characteristic reflections, expressed in degrees 2θ°, at approximately 3.22, 4.95, 6.60, 8.27, 9.93, 11.61, 13.29, 20.02, 20.75, 21.33, 21.97, 23.41, 24.23, 37.21, 30.20, 33.73, 34.20, 38.98, 40.75, 42.57 (±0.2).

[0044] The NMR spectrum shows peaks at 5.9, 5.2, 4.5, 2.3, 2.1, 1.5, and 1.2 ppm.

[0045] In a third aspect, the present invention relates to a process for the preparation of a compound of formula (15).

[0046] With particular reference to the first aspect, the present invention relates to a method comprising the steps of: a) reacting a compound of formula (15) with a compound of formula (14) in the presence of a condensing agent to obtain a compound (26);

[0047] [ka] b) converting compound (26) into a group R by a catalytic reaction using a transition metal 14 to obtain a compound of formula (11). [ka]

[0048] In a more preferred embodiment, the present invention relates to a process for the preparation of ODDA-paclitaxel (5), comprising the steps of: a') reacting a compound of formula (15) with paclitaxel (2) in the presence of a condensing agent to obtain a compound (27);

[0049] [ka] b') A group R is formed by a catalytic reaction using a transition metal 14 to obtain ODDA-paclitaxel of formula (5).

[0050] [ka]

[0051] In steps a) and a'), the condensing agent used is typically N,N'-dicyclohexylcarbodiimide (DCC), ethyldimethylaminopropylcarbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), N,N'-di-tert-butylcarbodiimide, 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC) and N-cyclohexyl-N'-(2-morpholinoethyl)-carbodiimide methyl-p-toluenesulfonate (CMC); preferably ethyldimethylaminopropylcarbodiimide (EDC).

[0052] The solvent used in steps a) and a') is typically selected from dichloromethane (CH2Cl2), tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO), preferably dichloromethane (CH2Cl2).

[0053] In steps a) and a'), the reaction mixture is maintained at a temperature ranging from 0°C to 50°C, preferably from 20°C to 30°C.

[0054] In steps b) and b'), a transition metal is used as a catalyst for removing the protecting group, preferably a palladium catalyst selected from Pd(Ph3)4, Pd(dba)2, Pd2(dba)3, PdCl2, Pd(OAc)2, PdCl2(PPh3)2.

[0055] In steps b) and b'), a metal catalyst is used in combination with an organic base such as morpholine, pyridine, pyrrolidine, or in combination with triphenylphosphine (PPh3) and a reducing agent such as ammonium formate, triethylammonium formate, etc.

[0056] Typically, Pd(PPh3)4 is used in combination with an organic base such as morpholine, pyridine, or pyrrolidine; Pd(dba)2 and Pd2(dba)3 are used in combination with 2-3 equivalents of PPh3 and an organic base such as morpholine, pyridine, or pyrrolidine; PdCl2, Pd(OAc)2, and PdCl2(PPh3)2 are used in combination with 2-3 equivalents of PPh3 and a reducing agent such as ammonium formate or triethylammonium formate.

[0057] Said mild deprotection conditions are particularly advantageous because, unlike known conditions, they avoid the use of fluorine-based reagents, which are highly toxic and require ad-hoc industrial-scale equipment. Moreover, said metal catalysts allow the removal of protecting groups in a highly selective manner without affecting other ester functions present in compounds of formulae (26) and (27), thus also preventing the formation of further undesired impurities.

[0058] The catalyst used is removed at the end of the reaction by washing with an aqueous solution of cysteine, cysteine ​​hydrochloride, N-acetylcysteine ​​or charcoal.

[0059] The compound of formula (14) obtained in step b) and ODDA-paclitaxel (5) obtained in step b') are isolated by dissolving in an alcohol such as methanol, ethanol or isopropanol, preferably in methanol, followed by precipitation, preferably from an anti-solvent such as water. This step is particularly advantageous since in known methods ODDA-PTX (5) is obtained in the form of a glassy solid after removal of the solvent and concentration to dryness, whereas in the method according to the invention, after precipitation and filtration, it is obtained in the form of a powder. The isolation of compound (5) by precipitation and filtration reduces the time and cost involved in concentration to dryness and also simplifies the process considerably, since it provides the product in a non-glassy form. The solid obtained in said glassy form is usually difficult to manage on an industrial scale, since in view of its extreme hardness it can damage the equipment and is difficult to recover, leading to loss of the product or the need to repeat the dissolution and concentration steps.

[0060] Between steps a)-b) and a')-b'), the process according to the invention comprises dissolving the crude reaction product obtained in step a)-a') in an aqueous-alcoholic solution obtained by mixing water with an alcohol selected from ethanol, propanol, isopropanol, butanol, isobutanol and tert-butanol, preferably methanol, and washing the solution obtained with a non-polar solvent selected from pentane, hexane, heptane, cyclohexane and toluene, preferably heptane.

[0061] When the starting compound of formula (14) is paclitaxel (2), washing with a non-polar solvent is surprisingly advantageous since it allows the compound of formula (8) ODDA-PTX-ODDA to be selectively removed without loss of the compound of formula (27). More specifically, as can be seen from the comparison in Table 1, the ODDA-PTX of formula (5) obtained by the method according to the invention is characterized by a much lower impurity content than the ODDA-PTX of formula (5) obtained by known methods, such as the method described in WO2021 / 007322.

[0062] [Table 2]

[0063] For clarity, "mixture of ODDAPTX isomers and epimers" refers to a mixture of compounds with the same molecular weight as ODDA-PTX that have been analyzed by LC_MS, but have not been individually separated and identified.

[0064] The process according to the invention allows obtaining ODDA-PTX of formula (5) in a yield of 98% and with a purity of 95-97% as determined by HPLC analysis according to the method reported in the Examples section. The process also allows obtaining ODDA-paclitaxel (5) in amorphous form.

[0065] With particular reference to the third embodiment, compound (15) can be obtained by reacting a compound of formula (6) with an alcohol of formula (28), wherein R 14 are preferably allyl, benzyl and 1,1-dimethyl-2-butenyl and are catalyzed by Lewis or Brønsted acids such as p-toluenesulfonic acid, sulfuric acid, HfCl4, FeCl3, Sc(OTf)3 and thio(acac)2, preferably p-toluenesulfonic acid, to give compounds of formula (15).

[0066] [ka] Typically, the alcohol of formula (28) can be used in the range of 0.5 to 5 equivalents, preferably 2 equivalents.

[0067] Typically the solvent used is selected from xylene, mesitylene, ethylbenzene and preferably toluene.

[0068] Typically, the reaction mixture is heated to a temperature range of from 50 to 150°C, preferably from 80 to 110°C.

[0069] Usually, the reaction mixture is cooled to a temperature of -10 to 30°C, preferably 20 to 25°C.

[0070] The protection step of the compound of formula (6) according to the present invention is particularly advantageous, in fact, the protection described in WO2017 / 053391 and WO2021 / 007322 requires a chromatographic step for purification and isolation of the resulting compound of formula (9), whereas the compound of formula (15) is purified by successive extractions with a solvent and finally crystallization. In particular, in a first embodiment, the purification and isolation step of the compound of formula (15) comprises a step comprising crystallization of said compound in a linear or branched C2-C5 alkyl alcohol, and the purification and isolation step of the compound of formula (15) preferably comprises the following steps:

[0071] l) The compound of formula (15) is dissolved in a linear or branched C2-C5 alkyl alcohol at a temperature in the range of 25-80° C. to obtain a solution B1. m) Solution B1 is cooled to crystallize the compound of formula (15) to obtain suspension C1. n) Isolating the crystallized compound of formula (15) from suspension C1.

[0072] Typically, in step l), the alcohol is 2-propanol, which can be used alone or in admixture with an organic base selected from Et3N, pyridine, DMAP and imidazole, preferably Et3N. When 2-propanol is mixed with a base, the base is present in an amount ranging from 0.5 to 2.5 equivalents, preferably 0.8 to 1.4 equivalents, relative to the acid used to catalyze the reaction of the compound of formula (6) with the compound of formula (28). When 2-propanol is used alone, step l) is preceded by crystallization of the crude compound of formula (15) from a polar aprotic solvent selected from DMF, DMSO, acetone and ethyl acetate, preferably acetone.

[0073] Typically, in step l), the solution is heated to a temperature in the range of 40 to 45°C.

[0074] Typically, in step m), the solution is cooled to room temperature, which can be reached directly or in one or more steps including maintaining the solution at a temperature in the range of room temperature to 45° C. The solution is preferably cooled from 45° C. to 40° C., from 40° C. to 34° C., and from 34° C. to room temperature.

[0075] In another embodiment, the compound of formula (15), preferably R 14 The purification and isolation process for compounds where is allyl comprises the following steps. c) dissolving the crude compound of formula (15) in a basic water-alcohol solution to obtain solution A. d) A process of washing solution A with a non-polar solvent to obtain solution B (aqueous-alcoholic phase) and solution C (organic phase). e) Acidifying solution B to pH=3 to obtain suspension D. f) Extracting suspension D with a non-polar solvent to obtain solution E. g) concentrating solution E at low pressure to obtain a partially purified compound of formula 15. h) suspending the partially purified compound of formula (15) in alcohol to obtain suspension F. i) heating suspension F to obtain solution G. j) cooling solution G to crystallize the compound of formula (15) to obtain suspension H. k) isolating the crystallized compound of formula (15) from solution H.

[0076] For clarity, in step c), "basic water-alcohol solution" means a solution of water and an alcohol selected from methanol, ethanol, propanol and isopropanol, preferably methanol, to which an inorganic base selected from NaHCO3 and KHCO3 is added until the pH is between 8 and 9.

[0077] Typically, in step d), the non-polar solvent is selected from pentane, hexane, heptane, cyclohexane, toluene and benzene, preferably heptane.

[0078] Typically, in step e), the acid used is a mineral acid such as HF, HCl, HBr, H2SO4, HNO3 or H3PO4, preferably HCl.

[0079] Typically, in step f), the non-polar solvent is selected from pentane, hexane, heptane, cyclohexane, toluene and benzene, preferably toluene.

[0080] Typically, in step h), the alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, iso-butanol and tert-butanol, preferably methanol.

[0081] Typically, in step i) the solution is heated to 30-90°C, preferably 35-60°C, more preferably 40°C.

[0082] The protection step of the compound of formula (6) according to the invention is further advantageous since it allows the reduction of the amount of the compound of formula (29) present as an impurity in compound (6), the corresponding diprotected compound of formula (30) and the monoprotected compound of formula (31) as well as the unreacted compound of formula (6) and compound of formula (28). In particular, the amount of each of the compounds (6) and (28) to (31), as assessed by HPLC analysis as area %, is reduced by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%. For clarity, the amount of each of the compounds is reduced independently of each other. For example, the amount of the compound of formula (6) can be reduced by 90%, while the amount of the compound of formula (30) can be reduced by 60%.

[0083] [ka]

[0084] Furthermore, elimination of chromatography steps that are present in known methods but that do not efficiently remove undesired compounds (28)-(31) is advantageous as it results in a more easily scalable method. EXAMPLES

[0085] The following commercially available reagents and solvents were used: Absolute ethanol (“EtOH abs.”) (GC purity >99%); Ethanol (“EtOH”) (GC purity ≥ 95%), (technical grade); Ethyl acetate ("AcOEt") (GC purity >95%), (technical grade); Dichloromethane ("CH2Cl2") (stabilized with amylene, purity ≥ 98%); Potassium carbonate (“K2CO3”) (purity ≥ 95%); Sodium chloride ("NaCl") (95% purity or greater), (Technical grade); 37% hydrochloric acid ("HCl 37%"); Toluene ("PhMe") (HPLC purity ≥ 99.7%); Methanol ("MeOH") (HPLC purity ≥ 999%.) Tetrahydrofuran ("THF") (HPLC purity ≧99.9%) Palladium acetate ("Pd(OAc)2") 98%; Triphenylphosphine ("PPh3") (HPLC purity ≥ 99%); Triethylamine ("Et3N") (GC purity ≥ 99%); Formic acid ("HCOOH") (purity ≥ 98%); Allyl alcohol (GC purity ≥ 99.5%); Heptane (GC purity ≥ 99%).

[0086] The HPLC analysis was performed using a Zorbax SB-C8 column (l = 150 mm;, id = 4.6 mm, particle size = 3.5 μm) and solvents A (water + 100 ppm HCOOH) and B (CH3CN + 100 ppm HCOOH) as mobile phases, using an HPLC system consisting of a quaternary pump, a thermostatic autosampler, a column compartment and a UV / VIS detector.

[0087] Example 1 - Preparation of mono-allyl-octadecanedioic acid (allyl-ODDA) Allyl alcohol (1.85 g, 31.8 mmol) was added to a solution of ODDA (5 g, 15.9 mmol) and pTSA-H2O (150 mg, 0.79 mmol) in toluene (185 mL) and heated to 90 °C, the solution was first kept at reflux for 4 h to remove water by azeotropic distillation, then cooled to room temperature, filtered through Celite, and finally concentrated at low pressure. The obtained residue was dissolved in a pH = 8 MeOH / H2O (150 mL) mixed solvent (1.26 g KHCO3) and washed with heptane (3 x 150 mL). The water-methanol phase was acidified to pH = 3 by adding 1 M hydrochloric acid until a suspension was obtained, followed by extraction with toluene (2 x 250 mL). The toluene phase was separated and concentrated at low pressure. The obtained residue was suspended in methanol and heated at 40 °C until complete dissolution, and finally cooled to room temperature to obtain a solid precipitate. The solid, isolated as a white powder, was isolated by filtration and dried at 40° C. for 24 hours (2.0 g, yield: 35%).

[0088] 1 H-NMR:5.9ppm(1H,m);5.2ppm(2H,m);4.5ppm(2H,m);2.3-2.1ppm(4H,m);1.5ppm(4H,m);1.2ppm(24H,m).

[0089] Example 2 - Preparation of Allyl-ODDA-paclitaxel Paclitaxel (3.33 g, 3.90 mmol), mono-allyl-ODDA (1.38 g, 3.90 mmol) and DMAP (52 mg, 0.43 mmol) were dissolved in CHCl (27 mL) under nitrogen atmosphere. A solution of EDC-HCl (1.34 g, 6.98 mmol) in CHCl (27 mL) was added dropwise to the solution in 30 min. The resulting reaction was stirred at room temperature for 1.5 h, then washed with 0.5 M hydrochloric acid (2x50 mL) and 15% saturated NaCl solution (50 mL), the organic phases were combined and concentrated under reduced pressure. The resulting solid was dissolved in MeOH (60 mL), water (6 mL) was added dropwise to the solution, and the aqueous-alcoholic solution was washed with heptane (3x30 mL), then saturated NaCl solution (70 mL) and finally extracted with CHCl (3x50 mL). After concentration under reduced pressure, the combined organic phase was dried to give a glassy white solid (4.43 g, yield=95%).

[0090] Example 3 - Preparation of ODDA-paclitaxel Under nitrogen atmosphere, a mixture of HCOOH (0.28 mL, 7.44 mmol) and Et3N (1.28 mL, 9.21 mmol) in THF (3.6 mL) was added to Pd(OAc)2 (8.3 mg, 0.04 mmol) and PPh3 (19.5 mg, 0.07 mmol) in THF (1.5 mL) at room temperature; diallyl-ODDA-paclitaxel solution was added to the mixture and kept under vigorous stirring, the resulting mixture was stirred until complete conversion. The reaction mixture was diluted with AcOEt (50 mL) and washed with 0.5 M hydrochloric acid (50 mL) and saturated NaCl solution (50 mL). The combined organic phase was concentrated under vacuum and the resulting residue was dissolved in CHCl2 (20 mL) and washed with an aqueous solution of cysteine ​​hydrochloride (0.3 g dissolved in 20 mL water) at 40° C. for 24 h. The organic phase was concentrated under vacuum and the resulting residue (4.1 g) was dissolved in EtOH (12 mL) and the solution was slowly added dropwise to water (36 mL) under stirring at room temperature for 1 h to obtain a suspension. The suspension was filtered and washed with a mixture of EtOH-H2O (1:3, 8 mL). The solid was obtained as a white powder and dried under vacuum at 45° C. for 24 h (2.82 g, yield=66%).

[0091] Example 4 - Preparation of mono-allyl-octadecanedioic acid (allyl-ODDA) ODDA (30 g, 95.4 mmol) and paratoluenesulfonic acid (0.9 g, 4.8 mmol) were suspended in toluene (1.1 L) and the resulting suspension was heated at 85-95 °C until a solution was obtained. Allyl alcohol (11 g, 189.4 mmol) was added in two portions to the solution and the mixture was heated at reflux for 4 h and water was removed by azeotropic distillation. The solution was cooled to room temperature and filtered through Celite. The filtered solution was concentrated by vacuum distillation (to about 150 mL). The concentrate was suspended in n-heptane (about 900 mL) and kept under stirring at room temperature for about 1 h. The suspension was then filtered and the solid residue was washed twice with heptane (60 mL). After 18 h under vacuum in a stove at 50 °C, 10.1 g of allyl-ODDA was obtained.

[0092] Example 5 - Crystallization of mono-allyl-octadecanedioic acid (allyl-ODDA) Allyl-ODDA (10.0 g, 28.2 mmol) was suspended in a mixture of 2-propanol (60 mL) and 0.45 M Et3N (1 mL, 0.45 mmol), and the resulting mixture was heated to 45°C until a clear solution was obtained, then cooled first to 40°C for 2 h, then to 34°C for 6 h, and finally to room temperature overnight. The solid formed was filtered and washed with 2-propanol (10 mL). After 16 h in a stove at 50°C under vacuum, 8.1 g of allyl-ODDA was obtained (crystallization yield = 80%, based on starting ODDA yield = 24%).

[0093] Example 6 - Preparation of Allyl-ODDA-paclitaxel Paclitaxel (19.5 g, 22.8 mmol), mono-allyl-ODDA (8.1 g, 22.8 mmol) and DMAP (280 mg, 2.29 mmol) were suspended in CHCl (157 mL) under nitrogen atmosphere. A solution of EDC-HCl (7.9 g, 41.2 mmol) in CHCl (157 mL) was added dropwise to the solution in 30 min. The resulting reaction was stirred at room temperature for 24 h, then washed with 0.5 M hydrochloric acid (310 mL) and 15% saturated aqueous NaCl (310 mL) and the organic phase was concentrated under reduced pressure. The resulting solid was dissolved in MeOH (390 mL) and water (40 mL) was added dropwise to the solution until a suspension was obtained. The aqueous-alcoholic suspension was washed with heptane (3x196 mL), then with a 6% saturated solution of NaCl (390 mL) and finally extracted with CH2Cl2 (3x50 mL). The combined organic phases were concentrated under reduced pressure and dried to give a spongy white solid (26 g, yield=95%).

[0094] Example 7 - Preparation of ODDA-paclitaxel Under nitrogen atmosphere, a mixture of HCOOH (1.68 mL, 44.5 mmol) and Et3N (7.42 mL, 53.4 mmol) in THF (21 mL) was added to Pd(OAc)2 (50 mg, 0.22 mmol) and PPh3 (115 mg, 0.44 mmol) in THF (4 mL) at room temperature, a solution of allyl-ODDA-paclitaxel (26 g, 21.8 mol) in THF (52 mL) was added to the mixture and kept under vigorous stirring, and the resulting mixture was stirred until complete conversion while heating to 50° C. The reaction mixture was diluted with AcOEt (500 mL) and washed with 1 M hydrochloric acid (500 mL) and 6% saturated aqueous NaCl (500 mL). The combined organic phase was concentrated under vacuum and the resulting residue was dissolved in CHCl (50 mL) and washed with aqueous cysteine ​​hydrochloride (5 g in 50 mL water) at 40° C. for 24 h. The organic phase was concentrated under vacuum until a solid was obtained. After 16 h on a stove under vacuum at 50° C., 25 g of ODDA-PTX was obtained (yield=98%).

[0095] Example 8 (Comparative Example) - Preparation of mono-TIPS-octadecanedioic acid (TIPS-ODDA) ODDA (5 g, 15.9 mmol) was dissolved in DMF (75 mL) at 60° C., TIPS-Cl (3.0 g, 15.6 mmol) and Et3N (2.2 mL, 15.6 mmol) were added to the solution, and the resulting mixture was left under stirring overnight. The mixture was filtered and dried. The residue was purified on silica using a 1:50 THF:DMC solvent mixture. Purification gave 217 mg of TIPS-ODDA as an oil.

[0096] The remaining fraction from the column was purified again by silica gel column chromatography using an elution gradient of THF:DMC=1:100→2.5:100 to obtain 1.28 g of oily TIPS-ODDA.

Claims

1. A method for preparing a compound of formula (11): 【Chemical 1】 a) reacting a taxane of formula (14) 【Chemistry 2】 reacting with a compound of formula (15), 【Chemistry 3】 where R １ , R ３ , R ４ , R ８ and R ９ are the same or different and are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl, which in turn may be substituted by one or more groups G which are the same or different from one another, or may be substituted alternately with one or more groups G, where G=-OH, -SH, -NH ２ , halogen, -CN, -NO ２ , -OR １２ , -SR １２ , -NHR １２ , -NR １２ R １３ , >C=O, >C=S, >C=NH, >C=NR １２ , -C(O)R １２ , -C(O)H, -C(O)OH, -C(O)NH ２ , —C(O)halogen, —C(O)OR １２ , -C(O)SR １２ , —C(O)NHR １２ , —C(O)NR １２ R １３ , -OC(O)OR １２ , -OC(O)NHR １２ , -NHC(O)NHR １２ or -NHC(S)NHR １２ and R ２ , R ６ , R ７ , R １０ and R １１ are the same or different and are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl, which in turn may be substituted by one or more groups G' which are the same or different from each other, or may be substituted alternately with one or more groups G', where G'=-OH, -SH, -NH ２ , halogen, -CN, -NO ２ , -OR １２ , -SR １２ , -NHR １２ , -NR １２ R １３ , >C=O, >C=S, >C=NH, >C=NR １２ , -C(O)R １２ , -C(O)H, -C(O)OH, -C(O)NH ２ , —C(O)halogen, —C(O)OR １２ , -C(O)SR １２ , —C(O)NHR １２ , —C(O)NR １２ R １３ , -OC(O)OR １２ , -OC(O)NHR １２ , -NHC(O)NHR １２ or -NHC(S)NHR １２ and R ５ = H, alkyl, alkenyl or cycloalkyl; R １２ and R １３ are the same or different and are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl, which in turn may be substituted by one or more groups X which are the same or different from one another, or may be substituted alternately with one or more groups X, where X=-CH ３ , -CH ２ -, -CH<, -OH, -SH, -NH ２ , halogen, -CN, -NO ２ , -O-, -S-, -NH-, -N<, >C=O, >C=S, >C=NH, >C=N-, -C(O)H, -C(O)OH, -C(O)NH ２ , -C(O) halogen, -C(O)O-, -C(O)S-, -C(O)NH-, -C(O)N<, -OC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(S)NH-; R ２ and R ５ may together form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted with one or more groups G or alternatingly substituted with one or more groups G, where G is as defined above; R ６ and R ７ may be taken together to form a group =Y, where Y==CH ２ , =O, =S, =NH, =N-; R １ and R ６ may together form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted by or alternating with one or more identical or different groups G, where G is as defined above; R ８ and R １０ may together form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted by or alternating with one or more identical or different groups G, where G is as defined above; and R １４ is a protecting group that can be removed by a transition metal catalyzed reaction, b) removing the protecting group; A method comprising:

2. 10. The method of claim 1, wherein in the taxane of formula (14), 【Chemistry 4】 R １ , R ３ , R ４ , R ８ and R ９ are the same or different, H, C １ ~C １０ Alkyl, C ２ ~C １０ Alkenyl, C ２ ~C １０ Alkynyl, C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl and C ３ ~C １０ heteroaryl, optionally substituted with one or more identical or different groups G or alternatingly substituted with one or more identical or different groups G, where G is as defined above; R ２ , R ６ , R ７ , R １０ and R １１ are the same or different, H, C １ ~C １０ Alkyl, C ２ ~C １０ Alkenyl, C ２ ~C １０ Alkynyl, C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, —OH, —SH, —NH ２ , —NH— and —N<, optionally substituted by one or more groups G′ which are the same or different, or alternately substituted with one or more groups G′, where G′ is as defined above; R ５ = H, C １ -C ５ Alkyl, C ２ -C ５ Alkenyl, C ２ -C ５ Alkynyl or C ３ -C ６ cycloalkyl; R ２ and R ５ may together form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted by one or more groups G or alternating with one or more groups G, where G is as defined above; R ６ and R ７ may be taken together to form a group =Y, where Y==CH ２ , ═O, ═S, ═NH or ═N—; R １ and R ６ may be taken together to form a 3-, 4-, 5- or 6-membered cycloalkyl, optionally substituted by one or more groups G or alternating with one or more groups G, where G is as defined above; method.

3. 3. The method of claim 1 or 2, wherein the taxane of formula 14 is selected from paclitaxel (2), docetaxel (3), cabazitaxel (4), larotaxel (16), orthotaxel (17), BMS-184476 (18), tesetaxel (19), mirataxel (20), SB-T-1214 (21), SB-T-1216 (22), SB-T-121602 (23), SB-T-12854 (24), and docetaxel-f3-t-Boc (25). 【Table 1】

4. R １４ The method of claim 1, wherein is allyl or 1,1-dimethyl-2-butenyl.

5. R １４ The method of claim 1 or 4, wherein is allyl.

6. 10. The method of claim 1, comprising the steps of: a) reacting a compound of formula (15) with a compound of formula (14) in the presence of a condensing agent to obtain a compound (26); 【Chemistry 5】 b) converting compound (26) into a group R １４ to obtain the ODDA-taxane of formula (11). 【Chemistry 6】

7. 7. The method of claim 6, comprising the steps of: a') reacting monoprotected octadecanedioic acid of formula (15) with paclitaxel (2) in the presence of a condensing agent to obtain compound (27); 【Chemistry 7】 b') forming a group R by a catalytic reaction using a transition metal １４ to obtain ODDA-paclitaxel of formula (5). 【Chemistry 8】

8. The metal catalyst is Pd(Ph ３ ) ４ , Pd(dba) ２ , Pd ２ (dba) ３ , PdCl ２ , Pd(OAc) ２ and PdCl ２ (PPh ３ ) ２ The method of claim 1 , wherein the compound is selected from the group consisting of:

9. 10. The method of claim 1, comprising washing the compound of formula (11) with a non-polar solvent selected from pentane, hexane, heptane, cyclohexane and toluene.

10. 10. The method of claim 1, comprising isolating the compound of formula (11) by precipitation.

11. 7. The method of claim 6, wherein the compound of formula (11) contains less than 10% of compounds of formulas (12a) and (12b). 【Chemistry 9】

12. 8. The method of claim 7, wherein the compound of formula (5) contains less than 10% of the compound of formula (8). 【Chemistry 10】

13. A process for preparing a compound of formula (15), comprising: 【Chemistry 11】 A method for reacting a compound of formula (6) with a compound of formula (28): 【Chemistry 12】 Here, R １４ is allyl, benzyl or 1,1-dimethyl-2-butenyl.

14. 14. The method of claim 13, comprising a crystallization step.

15. 15. The method of claim 14, comprising washing the compound of formula (15) with a non-polar solvent selected from pentane, hexane, heptane, cyclohexane, toluene and benzene.

16. Compound represented by formula (15): 【Chemistry 13】 Here, R １４ is allyl or 1,1-dimethyl-2-butenyl.

17. Amorphous form of ODDA-PTX (5).

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