U.S. patent application number 11/975511 was filed with the patent office on 2008-05-08 for crystalline forms of docetaxel and process for preparation thereof.
This patent application is currently assigned to Scinopharm Singapore PTE Ltd.. Invention is credited to Shu-Ping Chen, Meng-Fen Ho, Tsung-Yu Hsiao, Yuan-Xiu Liao, Chia-Ning Lin, Yu-Li Lin.
Application Number | 20080108693 11/975511 |
Document ID | / |
Family ID | 39325127 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108693 |
Kind Code |
A1 |
Liao; Yuan-Xiu ; et
al. |
May 8, 2008 |
Crystalline forms of docetaxel and process for preparation
thereof
Abstract
New anhydrous crystalline form of docetaxel and process of
making anhydrous docetaxel and docetaxel trihydrate are
provided.
Inventors: |
Liao; Yuan-Xiu; (Kaohsiung
City, TW) ; Ho; Meng-Fen; (Anding Township, TW)
; Chen; Shu-Ping; (Kaohsiung City, TW) ; Lin;
Chia-Ning; (Pingtung City, TW) ; Lin; Yu-Li;
(Yongkang City, TW) ; Hsiao; Tsung-Yu; (Neimen
Township, TW) |
Correspondence
Address: |
COHEN, PONTANI, LIEBERMAN & PAVANE
551 FIFTH AVENUE
SUITE 1210
NEW YORK
NY
10176
US
|
Assignee: |
Scinopharm Singapore PTE
Ltd.
Singapore
SG
068912
|
Family ID: |
39325127 |
Appl. No.: |
11/975511 |
Filed: |
October 19, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60853341 |
Oct 20, 2006 |
|
|
|
Current U.S.
Class: |
514/449 ;
549/510 |
Current CPC
Class: |
C07D 305/14 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
514/449 ;
549/510 |
International
Class: |
A61K 31/337 20060101
A61K031/337; C07D 305/14 20060101 C07D305/14; A61P 35/00 20060101
A61P035/00 |
Claims
1. Crystalline anhydrous
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol characterized
by a powder x-ray diffraction pattern with peaks at about 8.0,
12.4, and 16.8.+-.0.2 degrees two-theta.
2. The crystalline anhydrous
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1
further characterized by a powder x-ray diffraction pattern with
peaks at about 11.3, 13.8, 15.4, 20.3, and 23.3.+-.0.2 degrees
two-theta.
3. The crystalline anhydrous
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1
further 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.+-.0.2 degrees two-theta.
4. The crystalline anhydrous
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1
characterized by a powder x-ray diffraction pattern as
substantially depicted in FIG. 3.
5. The crystalline anhydrous
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1
characterized by a powder x-ray diffraction pattern as
substantially depicted in FIG. 4.
6. The crystalline anhydrous
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1
further characterized by an infrared spectrum having bands at about
710, 1248, 1723, 2978, and 3430 (cm.sup.-1).
7. The crystalline anhydrous
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1
further characterized by an infrared spectrum as substantially
depicted in FIG. 10.
8. A process of producing crystalline
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol comprising the
steps of: coupling an oxazole intermediate of formula I: ##STR1##
with a baccatin III derivative of formula II: ##STR2## to produce a
compound of formula III: ##STR3## acidifying the compound of
formula III to produce a compound of formula IV: ##STR4##
protecting the compound of formula IV to form a compound of formula
V: ##STR5## deprotecting the compound of formula V obtain a
compound of formula VI: ##STR6## ozonolysing the compound of
formula VI to obtain a compound of formula VII: ##STR7## proceeding
condensation of the compound of formula VII to obtain crude
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol: ##STR8##
crystallizing the crude
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol to obtain the
crystalline N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl
taxol.
9. Crystalline N-debenzoyl-N-tert-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.
10. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl
taxol trihydrate of claim 9 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.
11. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl
taxol trihydrate of claim 9 further characterized by a powder x-ray
diffraction pattern as substantially depicted in FIG. 14.
12. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl
taxol trihydrate of claim 9 further characterized by an infrared
spectrum having bands at about 710, 1268, 1737, 2981, and 3374
(cm.sup.-1).
13. The crystalline N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl
taxol trihydrate of claim 9 further characterized by an infrared
spectrum pattern as substantially depicted in FIG. 19.
14. A process of preparing anhydrous docetaxel comprising the steps
of: (a) combining docetaxel and halohydrocarbon to from a solution;
and (b) adding an antisolvent to the solution to precipitate the
crystalline.
15. The process of claim 14 wherein the halohydrocarbon is
chlorohydrocarbon.
16. The process of claim 15 wherein the chlorohydrocarbon is
dichloromethane
17. The process of claim 14 wherein the antisolvent is selected
from the group consisting of C3-C8 linear and branched alkanes.
18. The process claim 14 wherein the antisolvent is n-heptane.
19. The process of claim 14 comprising a step of maintaining the
temperature of the solution of docetaxel, halohydrocarbon, and
antisolvent at about 25-40.degree. C.
20. The process of claim 14 further comprising a step of cooling
the solution to about 0-30.degree. C. to precipitate the
crystalline.
21. A process of producing docetaxel trihydrate comprising: a)
combining docetaxel and acetonitrile; b) heating the mixture of
step (a) to about 30-60.degree. C.; c) adding water to the mixture
of the heated mixture of step b); d) cooling the mixture of c) to
about 10-30.degree. C. to obtain a slurry; and e) filtering,
washing, and drying the slurry of step (d) to obtain docetaxel
trihydrate.
22. A composition comprising a therapeutically effective amount of
the crystalline anhydrous docetaxel of claim 1 and at least one
pharmaceutically acceptable excipient.
23. A method of treating a mammal suffering from a proliferative
disorder comprising administering to the mammal the composition of
claim 21.
Description
RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Patent Application Ser. No. 60/853,341 which was filed on Oct. 20,
2006. The content of the entire disclosure of U.S. Provisional
Patent Application Ser. No. 60/853,341 is herein explicitly
incorporated as reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to novel crystalline forms of
docetaxel and process for the preparation thereof.
[0004] 2. Description of the Related Art
[0005] Docetaxel is a compound found to exhibit anti-tumor
activity. It is presently sold under the trademark TAXOTERE.RTM..
While there are known techniques for synthesizing docetaxel, there
is still a need for improved chemical processes which can produce
this anti-cancer compound and in a form where the compound is
chemically stable.
SUMMARY OF THE INVENTION
[0006] In accordance with the first aspect of the present
invention, a novel crystalline 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.
[0007] Preferably, the novel crystalline anhydrous docetaxel is
further characterized by a powder x-ray diffraction pattern with
peaks at about 11.3, 13.8, 15.4, 20.3, and 23.3.+-.0.2 degrees
two-heta. More preferably, crystalline anhydrous docetaxel is
further 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 substantially depicted in FIG. 3 or FIG.
4.
[0008] It is surprisingly found that the crystalline anhydrous form
of docetaxel in accordance with the present invention is more
stable than trihydrated form (see FIG. 2). The crystalline
anhydrous form of 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 a proliferative disorder.
[0009] In accordance with the second aspect of the present
invention, 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 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.
[0010] In accordance with the third aspect of the present
invention, a process of producing docetaxel trihydrate is provided.
The process comprises a) combining anhydrous docetaxel, and
acetonitrile; b) heating the mixture of step a) to about
30-60.degree. C.; c) adding water to the mixture of the heated
mixture of step d); cooling the mixture of c) to about
10-30.degree. C. to obtain a slurry; and e) filtering, washing, and
drying the slurry of step d) to obtain docetaxel trihydrate.
[0011] The present application also provides a new process of
synthesizing docetaxel and new crystalline docetaxel trihydrate as
explained in detail below.
[0012] 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. 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] In the drawings:
[0014] FIG. 1 shows a semisynthetic process of making
docetaxel.
[0015] FIG. 2 illustrates the stability of crystalline anhydrous
docetaxel and docetaxel trihydrate.
[0016] FIG. 3 shows an X-ray powder diffraction pattern of
crystalline anhydrous docetaxel prepared in accordance with the
process described in the present application.
[0017] FIG. 4 lists x-ray diffraction peaks for crystalline
anhydrous docetaxel prepared in accordance with the process
described in the present application.
[0018] FIG. 5 also shows a semisynthetic process of making
docetaxel.
[0019] FIGS. 6-7 shows an X-ray powder diffraction pattern of
crystalline anhydrous docetaxel prepared in accordance with the
process described in the present application.
[0020] FIG. 8 lists x-ray diffraction peaks for crystalline
anhydrous docetaxel prepared in accordance with the process
described in the present application.
[0021] FIG. 9 shows DSC pattern of crystalline anhydrous docetaxel
prepared in accordance with the process described in the present
application.
[0022] FIGS. 10-13 show IR pattern of crystalline anhydrous
docetaxel prepared in accordance with the process described in the
present application.
[0023] FIGS. 14-15 shows an X-ray powder diffraction pattern of
crystalline docetaxel trihydrate prepared in accordance with the
process described in the present application.
[0024] FIG. 16 lists x-ray diffraction peaks for crystalline
docetaxel trihydrate prepared in accordance with the process
described in the present application.
[0025] FIG. 17 shows DSC pattern of crystalline docetaxel trihydate
prepared in accordance with the process described in the present
application.
[0026] FIGS. 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 EMBODIMENTS
[0027] As an example, the semisynthetic process used to make
docetaxel is outlined in the FIG. 1. This process comprise the
synthesis of a certain oxazolidine (A-5) from
(2R,3S)-3-phenylisoserine HCl as the starting material.
10-deacetyl-baccatin III that has 2,2,2-tri-chloroethoxy-carbonyl
protecting groups in both the 7 and 10 positions (SPT1141-M1) is
then esterified with the oxazolidine (A-5) in the presence of
dicyclohexylcarbodiimide and 4-dimethylaminopyridine in 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 .beta.-amino ester (SPT1141-M3).
T-butoxycarbonyl is attached to produce SPT1141-M4. The
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 acetic acid in tetrahydrofuran produces
crude docetaxel.
[0028] 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 solution is purified by chromatography
with acetone and n-heptane as the eluant. The purified solution is
concentrated under vacuum and the docetaxel is obtained by
filtering.
[0029] In Step 8b, recrystallization--anhydrous, the purified
docetaxel is dissolved in dichloromethane, n-heptane is added and
the solution is seeded with 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 mixing the anhydrous
docetaxel with acetonitrile and glacial acetic acid, adding water
at a temperature between 30 to 50.degree. 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 under
vacuum at 60.degree. C. to provide docetaxel trihydrate.
[0030] 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 FIG. 2. Also, the
anhydrous form 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 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.
[0031] More detailed description of each step of the process shown
in FIG. 2 is provided below.
[0032] Step 1: Protection
[0033] 10-Deacetyl baccatin III (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.degree. 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 60.degree. C., and
water is added for precipitation. The 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 dried
under vacuum at NMT 60.degree. C. to provide SPT1141 M1 (approx. 22
Kg).
[0034] Step 2-1: Hydrolysis
[0035] 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 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 is used directly in the next
step.
[0036] Step 2-2: Coupling Reaction
[0037] SPT1141 M1 (approx. 3.8 Kg), toluene (approx. 11 Kg),
4-dimethyiaminopyridjne (approx. 114 g), and
I,.sup.3-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 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 SPT11141 M2 in toluene solution, and the
mixture is used directly in the next step.
[0038] Step 3: Deprotection
[0039] Tetrahydrofuran (approx. 21 Kg) is added to the above
mixture. The solution is cooled to NMT 10.degree. C., and a
solution of hydrochloric acid in methanol is slowly added. The
mixture is stirred at below 40.degree. C. until the reaction is
complete. Ethyl acetate and sodium bicarbonate solution are then
added to the resulting mixture. The organic layer is collected and
washed with sodium chloride solution. After concentration, SPT1141
M3 is dissolved in ethyl acetate, and the solution is used directly
in the next step.
[0040] Step 4: BOC Protection
[0041] DI-tert-butyl dicarbonate (approx. 1 Kg) is charged into a
suitable vessel containing a solution of 4-dimethylaminopyridine
(approx. 15 g) in SPT1141 M3 solution. After the reaction is
complete, .about.the solution is quenched with diluted hydrochloric
acid, and sodium chloride solution is added. The organic layer is
concentrated, and tetrahydrofuran is added to provide SPT1141 M4
solution. The solution is used directly in the next step.
[0042] Step 5: Deprotection
[0043] Zinc (approx. 2.7 Kg), glacial acetic acid (approx. 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 solvent swapped with isopropanol.
Water is added to the resulting solution. The solids are filtered
and washed to provide crude SPT1141 M5 (approx. 4 Kg).
[0044] Crude SPT1141 M5 (approx. 4 Kg) and dichloromethane (approx.
54 Kg) are charged into a suitable vessel. The 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).
[0045] Step 6: Ozonolysis
[0046] Ozone is added at NMT -40.degree. 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 -40.degree. C. After the
reaction is complete, dimethyl sulfide are added while maintaining
the temperature at NMT -40.degree. C., and the mixture is warmed to
20 to 30.degree. C. The mixture is concentrated, and water is added
for precipitation. The solids are filtered, washed, and dried to
provide SPT1141 M6 (approx. 4.6 Kg).
[0047] Step 7: Condensation
[0048] 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 Kg) in tetrahydrofuran
(approx. 110 Kg). The mixture Is then reacted under air at NMT
60.degree. C., and 1,2-phenylenediamine is added. After the
reaction is complete,.degree. the reaction mixture is concentrated
and solvent swapped with methanol at NMT 60.degree. C. The solid
by-products are removed, and the filtrate is mixed with a solution
of hydrochloric acid. The solids are isolated, washed, and dried to
provide crude docetaxel" (approx. 4 Kg).
[0049] Step 8a: Purification
[0050] Crude docetaxel (approx. 3 Kg) arid ethyl acetate (approx.
41 Kg) are charged into a suitable vessel. The mixture is stirred
at NMT 60.degree. 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.degree. C. until
the volume of residue is approx. 9 L Dichloromethane is then
charged to the residue to provide crude docetaxel solution (for
column chromatography).
[0051] Step 8b: Recrystallization--Anhydrous Form
[0052] Docetaxel for crystallization (about 1 Kg) and
dichioromethane are charge into a suitable vessel. The mixture is
stirred at NMT 45.degree. C. until the solid is dissolved, and
n-heptane is added for crystallization. The slurry is filtered,
washed, and dried to provide approx. 0.8 kg of docetaxel anhydrous.
The solid" is then used for the trihydrate formation.
[0053] Step 8c: Recrystallization (Docetaxel Trihydrate)
[0054] 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 NMT 45.degree. 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).
[0055] FIG. 5 also illustrates a semisynthetic process used to make
docetaxel.
[0056] The invention is not limited by the embodiments described
above which are presented as examples only but can be modified in
various ways within the scope of protection defined by the appended
patent claims.
* * * * *