AU2012203862B2 - Process for making docetaxel trihydrate - Google Patents

Abstract

A new crystalline form of docetaxel and process of making docetaxel trihydrate are provided. 3433991_1 (GE4latters) P80793AU.1

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant(s): ScinoPharm Singapore PTE, Ltd. Invention Title: Process for making docetaxel trihydrate The following statement is a full description of this invention, including the best method for performing it known to me/us: 2 5 PROCESS FOR MAKING DOCETAXEL TRIHYDRATE RELATED APPLICATIONS This application claims priority from U.S. Provisional Patent Application Serial Number 60/853,341 which was 10 filed on October 20, 2006. The content of the entire disclosure of U.S. Provisional Patent Application Serial Number 60/853,341 is herein explicitly incorporated as reference. 15 BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel crystalline forms of docetaxel and process for the preparation thereof. 20 2. Description of the Related Art Docetaxel is a compound found to exhibit anti-tumor activity. It is presently sold under the trademark TAXOTERE*. While there are known techniques for synthesizing docetaxel, there is still a need for 25 improved chemical processes which can produce this anti cancer compound and in a form where the compound is chemically stable. SUMMARY OF THE INVENTION The present invention describes a novel crystalline 30 anhydrous docetaxel characterized by a powder x-ray diffraction with peaks at about 8.0, 12.4, and 16.8 ± 0.2 degrees two-theta is found. Preferably, the novel crystalline anhydrous docetaxel is further characterized by a powder x-ray 35 diffraction pattern with peaks at about 11.3, 13.8, 15.4, 20.3, and 23.3 + 0.2 degrees two-theta. More preferably, crystalline anhydrous docetaxel is further 3433291 1 IGHMaterI PB0793 AU.I 3 5 characterized by a powder x-ray diffraction pattern with peaks at about 4.6, 9.2, 18.1, 18.4, 19.5, 20.8, 22.5, 23.7, 24.1, 28.3, and 30.6 and ± 0.2 degrees two-theta. The novel crystalline anhydrous docetaxel is preferably characterized by a powder x-ray diffraction pattern as 10 substantially depicted in Fig. 3 or Fig. 4. It is surprisingly found that the crystalline anhydrous form of docetaxel in accordance with the present invention is more stable than trihydrated form (see Figure 2). The crystalline anhydrous form of 15 docetaxel in accordance with the present invention in a therapeutically effective amount may be formulated with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition. Such a composition may be administered to a mammal, such as human, to treat 20 a proliferative disorder. There is also described a process of producing a crystalline anhydrous docetaxel is provided. The process comprises (a) combining docetaxel and halohydrocarbon to form a solution; and (b) adding an antisolvent to the 25 solution to precipitate the crystalline. The halohydrocarbon is prefererably chlorohydrocarbon, more preferably, dichloromethane. The antisovlent may be C3 C8 linear or branched alkanes, preferably, n-heptane. The present invention provides a process of 30 producing docetaxel trihydrate is provided. The process comprises a) combining anhydrous docetaxel, and acetonitrile; b) heating the mixture of step a) to about 30-60OC; c) adding water to the mixture of the heated mixture of step d);cooling the mixture of c) to about 10 35 30 C to obtain a slurry; and e) filtering, washing, and drying the slurry of step d) to obtain docetaxel trihydrate. 3301 I 1HMatedm PRn7QA All I 4 5 The present application also provides a new process of synthesizing docetaxel and new crystalline docetaxel trihydrate as explained in detail below. Accordingly, in a first aspect, the present invention provides crystalline N-debenzoyl-N-tert 10 butoxycarbonyl-10-deacetyl taxol trihydrate characterized by a powder x-ray diffraction pattern with peaks at about 8.8, 13.9, and 17.7 + 0.2 degrees two theta and an infrared spectrum having bands at about 710, 1268, 1737, 2981, and 3374 (cm'1). 15 In a second aspect, the present invention provides a process of producing docetaxel trihydrate comprising: a) combining docetaxel and acetonitrile; b) heating the mixture of step (a) to about 30-45OC; 20 c) adding water to the mixture of the heated mixture of step b); d) cooling the mixture of c) to about 10-300C to obtain a slurry; and e) filtering, washing, and drying the slurry of step (d) 25 to obtain docetaxel trihydrate. In a third aspect, the present invention provides docetaxel trihydrate prepared in accordance with the process as described above. In a fourth aspect, the present invention provides a composition comprising a therapeutically effective amount of crystalline N-debenzoyl-N-tert-butoxycarbonyl 30 10-deacetyl taxol trihydrate as described above, or docetaxel trihydrate as described above, and at least one pharmaceutically acceptable excipient. In a fifth aspect, the present invention provides use of crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 35 deacetyl taxol trihydrate as described above, or 5 5 docetaxel trihydrate as described above, or a composition as described above for the treatment of a proliferative disorder. In a sixth aspect, the present invention provides use of crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 10 deacetyl taxol trihydrate as described above, or docetaxel trihydrate as described above, or a composition as described above for the manufacture of a medicament for the treatment of a proliferative disorder. 15 In a seventh aspect, the present invention provides a method of treating a mammal suffering from a proliferative disorder comprising administering to the mammal a therapeutically effective amount of crystalline N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol 20 trihydrate as described above, docetaxel trihydrate as described above, or a composition as described above. The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of the disclosure. 25 For a better understanding of the invention, its operating advantages, and specific objects attained by its use, reference should be had to the drawing and descriptive matter in which there are illustrated and described preferred embodiments of the invention. 30 BRIEF DESCRIPTION OF THE DRAWINGS In the drawings: Figure 1 shows a semisynthetic process of making docetaxel. 35 Figure 2 illustrates the stability of crystalline anhydrous docetaxel and docetaxel trihydrate. U11091 I HMatArI PAM79 A[) 1 6 5 Figure 3 shows an X-ray powder diffraction pattern of crystalline anhydrous docetaxel prepared in accordance with the process described in the present application. Figure 4 lists x-ray diffraction peaks for 10 crystalline anhydrous docetaxel prepared in accordance with the process described in the present application. Figure 5 also shows a semisynthetic process of making docetaxel. Figures 6-7 shows an X-ray powder diffraction 15 pattern of crystalline anhydrous docetaxel prepared in accordance with the process described in the present application. Figure 8 lists x-ray diffraction peaks for crystalline anhydrous docetaxel prepared in accordance 20 with the process described in the present application. Figure 9 shows DSC pattern of crystalline anhydrous docetaxel prepared in accordance with the process described in the present application. Figures 10-13 show IR pattern of crystalline 25 anhydrous docetaxel prepared in accordance with the process described in the present application. Figures 14-15 shows an X-ray powder diffraction pattern of crystalline docetaxel trihydrate prepared in accordance with the process described in the present 30 application. Figure 16 lists x-ray diffraction peaks for crystalline docetaxel trihydrate prepared in accordance with the process described in the present application. Figure 17 shows DSC pattern of crystalline 35 docetaxel trihydate prepared in accordance with the process described in the present application. u432fli 1 IGHMattarmI P87Q3 Al I 7 5 Figures 18-21 show IR pattern of crystalline docetaxel trihydrate prepared in accordance with the process described in the present application. DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED 10 EMBODIMENTS As an example, the semisynthetic process used to make docetaxel is outlined in the Figure 1. This process comprise the synthesis of a certain oxazolidine (A-5) from (2R,3S)-3-phenylisoserine HCl as the starting 15 material. 10-deacetyl-baccatin III that has 2,2,2-tri chloroethoxy-carbonyl protecting groups in both the 7 and 10 positions (SPTll41-Ml) is then esterified with the oxazolidine (A-5) in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine in 20 toluene to produce an ester intermediate (SPT1141-M2). The ester intermediate is converted to docetaxel by a five-step procedure. Hydrochloric acid hydrolysis produces the P-amino ester (SPT1141-M3). T butoxycarbonyl is attached to produce SPT1141-M4. The 25 2,2,2-tri-chloroethoxy-carbonyl protecting groups are removed by reacting SPT1141-M4 with zinc and acetic acid to produce SPT1141-M5. Further removal of protecting groups by reaction with ozone in methanol and subsequently by reaction with o-phenylenediamine and 30 acetic acid in tetrahydrofuran produces crude docetaxel. In the step described as Step 8a, Purification, the crude docetaxel is dissolved in ethyl acetate, filtered, concentrated under vacuum to produce a residue, dichloromethane is added to dissolve the residue and the 35 solution is purified by chromatography with acetone and n-heptane as the eluant. The purified solution is 3433991_1 (GHMatters) P80793.AU.1 8 5 concentrated under vacuum and the docetaxel is obtained by filtering. In Step 8b, recrystallization - anhydrous, the purified docetaxel is dissolved in dichloromethane, n heptane is added and the solution is seeded with 10 docetaxel seed. The solution is cooled and the resulting slurry is filtered and the wet cake is dried to provide anhydrous docetaxel. The resulting anhydrous docetaxel can be further converted to the trihydrate form in Step 8c, recrystallization (trihydrate form) by 15 mixing the anhydrous docetaxel with acetonitrile and glacial acetic acid, adding water at a temperature between 30 to 50 0 C, then adding more water and seeding with docetaxel seed. The resulting slurry is then filtered and washed with water and the wet cake is dried 20 under vacuum at 60 0 C to provide docetaxel trihydrate. We surprisingly found that the anhydrous form of docetaxel is more stable (2168-115-16) than trihydrated form (1883-12-11, 1883-12-21, 2016-109-05) in acetonitrile. See Figure 2. Also, the anhydrous form 25 is more stable in acetonitrile than in acetonitrile/water (9/1). These data showed that docetaxel is less stable in co-water solvent. Docetaxel is more stable in non-water solvent than co-water solvent (ACN/water/acetic acid). Further more, an 30 impurity of docetaxel, 7-epi-docetaxel, is generated more rapidly in co-water solvent than in non-water solvent. The growth of 7-epi-docetaxel can be suppressed by the addition of acetic acid. More detailed description of each step of the 35 process shown in Fig. 2 is provided below. 3433991_1 (GHMatters) P80793.AU.1 9 5 Step 1: Protection 10-Deacetyl baccatin Ill (approx. 14 Kg), pyridine (approx. 137 Kg), and 2,2,2-trichloroethyl chloroformate (approx. 14 Kg) are charged into a suitable vessel. The resulting mixture is stirred at not more than (NMT) 10 10 0 C. After the reaction is complete, the solution is quenched with water followed by extraction with dichloromethane; the organic layer is separated and washed with water. The organic layer is concentrated at NMT 600C, and water is added for precipitation. The 15 solids are collected and washed with water. The wet cake is then suspended in ethyl acetate and heptanes are added. The solids are isolated, washed, and dned under vacuum at NMT 600C to provide SPT1141 M1 (approx. 22 Kg). 20 Step 2-1: Hydrolysis SPT2039 A4 (approx. 2.7 Kg), tetrahydrofuran (approx. 11 Kg), and about 1 N lithium hydroxide solution (approx. 6.6 Kg) are charged into a suitable vessel. The mixture is stirred. After the reaction is 25 complete, toluene and hydrochloric acid are added to adjust the mixture to pH < 3. The organic layer is washed with sodium chloride solution, and magnesium sulfate is added to remove water. The filtrate is concentrated to provide SPT2039 A5 in toluene solution, and the mixture 30 is used directly in the next step. Step 2-2: Coupling Reaction SPT1141 M1 (approx. 3.8 Kg), toluene (approx. 11 Kg), 4-dimethyiaminopyridjne (approx. 114 g), and 1,3 35 dicyclohexylcarbondiimide (approx. 1.3 Kg) are added to the mixture from step 2-1 The reaction mixture is stirred. After the reaction is complete, the reaction UAI'00 i IrH t ra P2n7Q' Al 1 10 5 mixture is quenched with hydrochloric acid. The slurry is filtered, and the filtrate is collected and separated. The organic layer is washed with sodium bicarbonate solution followed by water. The organic phase is concentrated to provide SPTlll41 M2 in toluene 10 solution, and the mixture is used directly in the next step. Step 3: Deprotection Tetrahydrofuran (approx. 21 Kg) is added to the above mixture. The solution is cooled to NMT 10C, and a 15 solution of hydrochloric acid in methanol is slowly added. The mixture is stirred at below 40 0 C until the reaction is complete. Ethyl acetate and sodium bicarbonate solution are then added to the resulting mixture. The organic iayer is collected and washed with 20 sodium chloride solution. After concentration, SPTll41 M3 is dissolved in ethyl acetate, and the solution is used directly in the next step. Step 4. BOC protection Dl-tert-butyl dicarbonate (approx. 1 Kg) is charged 25 into a suitable vessel containing a solution of 4 dimethylaminopyridine (approx. 15 g) in SPTl141 M3 solution. After the reaction is complete,- the solution is quenched with diluted hydrochloric acid, and sodium chloride solution is added. The organic layer is 30 concentrated, and tetrahydrofuran is added to provide SPT1141 M4 solution. The solution is used directly in the next step. Step 5: Deprotection Zinc (approx. 2.7 Kg), glacial acetic acid (approx. 35 10.8 Kg), tetrahydrofuran, and SPT1141 M4 solution are charged into a suitable vessel. After the reaction is complete, the mixture is filtered, and the filtrate is 11 5 solvent swapped with isopropanol. Water is added to the resulting solution. The solids are filtered and washed to provide crude SPT1141 M5 (approx. 4Kg). Crude SPT1141 M5 (approx. 4 Kg) and dichloromethane (approx. 54 Kg) are charged into a suitable vessel. The 10 solution is extracted with sodium chloride solution. Glacial acetic acid is added to the organic layer. The mixture is then concentrated and heptanes is added for crystallization. The solids are filtered, washed and dried to provide SPT1141 M5 (approx. 3.3 Kg). 15 Step 6: Ozonolysis Ozone is added at NMT -40 0 C to a suitable vessel containing a mixture of SPT1141 M5 (approx. 5.5 Kg), methanol (approx. 88 Kg), and glacial acetic acid (approx. 55 g) while maintaining the temperature at NMT 20 -40 0 C. After the reaction is complete, dimethyl sulfide are added while maintaining the temperature at NMT 40 0 C, and the mixture is warmed to 20 to 30 0 C. The mixture is concentrated, and water is added for precipitation. The solids are filtered, washed, and 25 dried to provide SPT1141 M6 (approx. 4.6 Kg). Step 7: Condensation Glacial acetic acid (approx. 5 Kg) is charged into a suitable vessel containing a solution of SPT1141 M6 (approx. 4.6 Kg) and 1 ,2-phenylenedjamine (approx. 1.8 30 Kg) in tetrahydrofuran (approx. 110 Kg). The mixture Is then reacted under air at NMT 60 0 C, and 1 ,2 phenylenediamine is added. After the reaction is complete, the reaction mixture is concentrated and solvent swapped with methanol at NMT 60 0 C. The solid by 35 products are removed, and the filtrate is mixed with a solution of hydrochloric acid. The solids are isolated, 33a3i1 i (GHMatare Pan7QA AU I 12 5 washed, and dried to provide crude docetaxel" (approx. 4 Kg). Step 8a: Purification Crude docetaxel (approx. 3 Kg) arid ethyl acetate (approx. 41 Kg) are charged into a suitable vessel. The 10 mixture is stirred at NMT 60 0 C and is filtered through a filter bed pie-coated with Celite, activated carbon, and activated acidic day. The filter bed is washed with ethyl acetate, and the filtrate is collected and concentrated under vacuum at NMT 60 0 C until the volume 15 of residue is approx. 9 L Dichloromethane is then charged to the residue to provide crude docetaxel solution (for column chromatography). Step 8b: Recrystallization -Anhydrous Form Docetaxel for crystallization (about 1 Kg) and 20 dichioromethane are charge into a suitable vessel. The mixture is stirred at NMT 45 0 C until the solid is dissolved, and n-heptane is added for crystallization. The slurry is filtered, washed, and dried to provide approx. 0.8kg of docetaxel anhydrous. The solid" is then 25 used for the trihydrate formation. Step 8c: Recrystallization (Docetaxel Trihydrate) Docetaxel anhydrous (about 0.8 Kg), acetonitriie (about 3.8 Kg) and glacial acetic acid (about 7.6 g) are charged into a suitable vessel. The mixture is heated to 30 NMT 45 0 C, and purified process water (about 9.6 Kg) is added for precipitation. The slurry is filtered, washed and dried under a moist environment to provide docetaxel trihydrate (about 0.7 Kg). Figure 5 also illustrates a semisynthetic process 35 used to make docetaxel. The invention is not limited by the embodiments described above which are presented as examples only but 3433991 1 (GHMatters) P80793 AU-1 13 5 can be modified in various ways within the scope of protection defined by the appended patent claims. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary 10 implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the 15 invention. It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in 20 Australia or any other country. 3433991 1 (GHMatters) P80793 AU.1

Claims (12)

1. Crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 deacetyl taxol trihydrate characterized by a powder x-ray 5 diffraction pattern with peaks at about 8.8, 13.9, and 17.7 + 0.2 degrees two-theta and an infrared spectrum having bands at about 710, 1268, 1737, 2981, and 3374 (cm~ 1 ).

2. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 ) deacetyl taxol trihydrate of claim 1 further characterized by a powder x-ray diffraction pattern with peaks at about 4.4, 11.0, and 22.2 + 0.2 degrees two-theta.

3. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 5 deacetyl taxol trihydrate of claim 1 or claim 2 further characterized by a powder x-ray diffraction pattern as substantially depicted in Figure 14.

4. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 ) deacetyl taxol trihydrate of any one of claims 1-3, further characterized by an infrared spectrum pattern as substantially depicted in Figure 19.

5. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 5 deacetyl taxol trihydrate of any one of claims 1-4, further characterized by endothermic peaks at about 78 and 168 0 C.

6. A process of producing docetaxel trihydrate comprising: .0 a) combining docetaxel and acetonitrile; b) heating the mixture of step (a) to about 30-450C; 15 c) adding water to the mixture of the heated mixture of step b); d) cooling the mixture of c) to about 10-30 0 C to obtain a slurry; and i e) filtering, washing, and drying the slurry of step (d) to obtain docetaxel trihydrate.

7. Docetaxel trihydrate prepared in accordance with the process of claim 6.

8. A composition comprising a therapeutically effective amount of crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 deacetyl taxol trihydrate of any one of claims 1-5, or docetaxel trihydrate of claim 7, and at least one pharmaceutically acceptable excipient.

9. Use of crystalline N-debenzoyl-N-tert-butoxycarbonyl

10-deacetyl taxol trihydrate of any one of claims 1-5, or docetaxel trihydrate of claim 7, or a composition of claim 8 for the treatment of a proliferative disorder. 0 10. Use of crystalline N-debenzoyl-N-tert-butoxycarbonyl 10-deacetyl taxol trihydrate of any one of claims 1-5, or docetaxel trihydrate of claim 7, or a composition of claim 8 for the manufacture of a medicament for the treatment of a 5 proliferative disorder.

11. A method of treating a mammal suffering from a proliferative disorder comprising administering to the mammal a therapeutically effective amount of crystalline N-debenzoyl-N 0 tert-butoxycarbonyl-10-deacetyl taxol trihydrate of any one of 16 claims 1-5, docetaxel trihydrate of claim 7, or a composition of claim 8.

12. Crystalline N-debenzoyl-N-tert-butoxycarbonyl-10 5 deacetyl taxol trihydrate as defined in claim 1, processes for producing it, compositions comprising it, or methods or uses involving it, substantially as herein described with reference to the accompanying drawings or examples.