U.S. patent application number 15/097071 was filed with the patent office on 2016-10-13 for process for the preparation of dicycloplatin.
This patent application is currently assigned to Syn-Nat Products Enterprise LLC. The applicant listed for this patent is Medoc Pharmaceutical Co., Ltd, Syn-Nat Products Enterprise LLC. Invention is credited to Xiaozhong Liu, Jirui Xi, Liang Zhang, Ye Zhao.
Application Number | 20160297842 15/097071 |
Document ID | / |
Family ID | 56895556 |
Filed Date | 2016-10-13 |
United States Patent
Application |
20160297842 |
Kind Code |
A1 |
Liu; Xiaozhong ; et
al. |
October 13, 2016 |
Process for the Preparation of Dicycloplatin
Abstract
The present invention relates to a process to prepare
dicycloplatin under mild reactive conditions and at fast reaction
rates. The process is reproducible and easy to scale up for
industrial application.
Inventors: |
Liu; Xiaozhong; (Potomac,
MD) ; Xi; Jirui; (North Brunswick, NJ) ; Zhao;
Ye; (North Brunswick, NJ) ; Zhang; Liang;
(North Brunswick, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Syn-Nat Products Enterprise LLC
Medoc Pharmaceutical Co., Ltd |
Edison
Changsha |
NJ |
US
CN |
|
|
Assignee: |
Syn-Nat Products Enterprise
LLC
Edison
NJ
Medoc Pharmaceutical Co., Ltd
Changsha
|
Family ID: |
56895556 |
Appl. No.: |
15/097071 |
Filed: |
April 12, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/US2015/025334 |
Apr 10, 2015 |
|
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15097071 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 15/0093
20130101 |
International
Class: |
C07F 15/00 20060101
C07F015/00 |
Claims
1. A process for preparing dicycloplatin of formula (I),
##STR00003## comprising: combining carboplatin with a corresponding
proportion of 1,1-cyclobutane dicarboxylic acid and a solvent to
form a suspension; separating formed precipitated solids from the
suspension; and drying the solids, wherein the solids comprise the
dicycloplatin of formula (I) without a detectable amount of
carboplatin present, and wherein the molar ratio of the carboplatin
and the 1,1-cyclobutane dicarboxylic acid in the combining step
ranges from about 1:1.15 to 1:50.
2. The process of claim 1, wherein the solids comprise
dicycloplatin of formula (I) without any amount of carboplatin
detectable by XRPD.
3. The process of claim 1, further comprising cooling the
precipitating solids before the separating step.
4. The process of claim 1, further comprising agitating the
suspension after the combining step and before the separating
step.
5. The process of claim 1, wherein the solids consist essentially
of dicycloplatin.
6. The process of claim 1, wherein the solids consist of
dicycloplatin.
7. The process of claim 1, wherein the solvent is water.
8. The process of claim 1, wherein the molar ratio of the
carboplatin and the 1,1-cyclobutane dicarboxylic acid in the
combining step ranges from about 1:15 to about 1:50.
9. The process of claim 1, wherein the molar ratio of the
carboplatin and the 1,1-cyclobutane dicarboxylic acid in the
combining step ranges from about 1:1.15 to 1:2.
10. The process of claim 1, wherein the proportion of the weight of
carboplatin in grams and the volume of the solvent in mL in the
combining step ranges from about 1:2 to about 1:50.
11. The process of claim 1, wherein the proportion of the weight of
the carboplatin in grams and the volume of the solvent in mL in the
combining step ranges from about 1:3 to about 1:5.
12. The process of claim 1, wherein the dicycloplatin has an X-ray
powder diffraction pattern substantially as depicted in FIG. 2.
13. The process of claim 1, wherein the reaction temperature of the
combining step ranges from 0.degree. C. to 80.degree. C.
14. The process of claim 1, wherein the reaction temperature of the
combining step ranges from 10 to 25.degree. C.
15. The process of claim 1, wherein the solvent is an organic
solvent selected from the group consisting of: tetrahydrofuran
(THF), dichloromethane (DCM), isopropanol, ethanol, ethyl acetate
(EtOAc), dimethylformamide (DMF), 1,4-dixoane, acetone, toluene,
isobutyl acetate, isopropyl acetate, chloroform, 2-methoxyethanol,
methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE),
1,2-dichloro ethane, and a mixture thereof.
16. The process of claim 1, wherein the solvent is a mixture of
water and an organic solvent selected from the group consisting of:
THF, DCM, isopropanol, ethanol, EtOAc, DMF, 1,4-dixoane, acetone,
and a mixture thereof.
17. The process of claim 12, wherein the reaction temperature of
the combining step ranges from 0.degree. C. to 80.degree. C.
18. The process of claim 12, wherein the reaction temperature of
the combining step ranges from 20 to 35.degree. C.
19. The process of claim 12, wherein the molar ratio of the
carboplatin and the 1,1-cyclobutane dicarboxylic acid in the
combining step ranges from 1:3 to about 1:50.
20. The process of claim 12, wherein the molar ratio of the
carboplatin and the 1,1-cyclobutane dicarboxylic acid in the
combining step ranges from 1:5 to 1:10.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a new process for preparing an
antitumor derivative of a double dicarboxylic acid diaminoplatin
complex, named as dicycloplatin.
BACKGROUND OF THE INVENTION
[0002] Cisplatin has been used widely in clinical medicine as an
antitumor drug since an antitumor effect was discovered for
cis-dichlorodiaminoplatin. Rosenberg et al. Nature, 1965, 205: 698;
Nature, 1972, 222: 385. Although a drug of this type exhibits
therapeutic effects in cancers such as genitourinary cancer,
nasopharyngeal cancer, cephalocircular cancer and lung cancer, it
is toxic and leads to severe side effects. Some undesirable
effects, such as nephrotoxicity, neurotoxicity, ototoxicity,
nausea, and vomiting, are all constraints to its dosage and long
term use. Carboplatin, one of the second-generation antitumor drugs
of platin analogues, has an antitumor spectrum similar to that of
cisplatin and is susceptible to cross drug-resistance. The
therapeutic effect of carboplatin is slightly inferior to that of
cisplatin. Although the toxicity and associated side effects of
carboplatin is significantly less than that of cisplatin,
myelosuppression still exists, and cisplatin is not stable as an
aqueous solution. As a result, active studies in search of highly
potent antitumor drugs from platin analogues with low toxicity and
broad-spectrum effects have continued.
[0003] Dicycloplatin (DCP) is a super molecule composed of
carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined
together by hydrogen bonds. The solubility and stability of
platinum complexes have a direct bearing on their activity,
toxicity and pharmacokinetics. Preclinical studies have shown that
DCP overcomes the problem of CBP instability in aqueous solution
while maintaining CBP's anticancer effects. Clinical evaluation in
a Phase I dose-escalation study in patients with tumors showed that
DCP was tolerated at doses ranging from 100 to 550 mg/m.sup.2 and
showed potential efficacy in Chinese cancer patients. DCP showed
favorable bioavailability and stability in vivo, with the
recommended Phase II dosage for DCP-containing chemotherapy being
450 mg/m.sup.2. DCP is currently being investigated as a
monotherapy in several cancer types, such as prostatic carcinoma,
and in combination with paclitaxel in a Phase II non-lung cancer
study. The chemical structure of DCP is shown as formula I:
##STR00001##
[0004] Dicycloplatin (DCP) was first reported in U.S. Pat. No.
6,699,901, which disclosed the chemical structure and process for
preparation of DCP.
[0005] The crystal structure of DCP has been determined and
reported in "Structural studies of dicycloplatin-an antitumor
supramolecule." Yang X. et al., Science China Chemistry, 40(5):
485-491 (2010), which shows dicycloplatin as a co-crystal composed
of carboplatin and 1,1-cyclobutane dicarboxylate.
[0006] However, the processes disclosed in U.S. Pat. No. 6,699,901,
which were tested by the inventors of the present invention, cannot
produce satisfying results and are difficult to scale up for
industrial-scale production. The preparation of dicycloplatin
according to the method of U.S. Pat. No. 6,699,901 produced a
mixture of carboplatin and dicycloplatin, resulting in high
toxicity and unacceptable products.
[0007] Therefore, it is desirable to provide robust and
easy-to-scale-up crystallization processes to efficiently obtain
pure dicycloplatin in high yield.
SUMMARY OF THE INVENTION
[0008] The present invention provides a surprisingly discovered new
process for preparing dicycloplatin with the benefits of easy
operation, mild reactive conditions, short reaction times and high
reproducibility.
[0009] Accordingly, the present invention provides a process for
preparing dicycloplatin, comprising: suspending per unit
carboplatin in a corresponding proportion of 1,1-cyclobutane
dicarboxylic acid and solvent(s); followed by crystallizing or
precipitating the dicycloplatin through stirring, evaporating the
solvent(s), and/or cooling.
[0010] An aspect of the invention is a process for preparing
dicycloplatin of formula (I),
##STR00002##
[0011] comprising: combining carboplatin with a corresponding
proportion of 1,1-cyclobutane dicarboxylic acid and a solvent to
form a suspension; separating formed precipitated solids from the
suspension; and drying the solids, wherein the solids comprise the
dicycloplatin of formula (I) without any amount of carboplatin
detectable by XRPD.
[0012] In an embodiment, the process further comprises cooling the
precipitating solids before the separating step.
[0013] In an embodiment, the process further comprises agitating
the suspension after the combining step and before the separating
step.
[0014] In an embodiment, the solids consist essentially of
dicycloplatin.
[0015] In an embodiment, the solids consist of dicycloplatin.
[0016] In an embodiment, the solvent used in the process is
water.
[0017] In an embodiment, the molar ratio of the carboplatin and the
1,1-cyclobutane dicarboxylic acid in the combining step ranges from
about 1:15 to about 1:50.
[0018] In an embodiment, the molar ratio of the carboplatin and the
1,1-cyclobutane dicarboxylic acid in the combining step ranges from
about 1:1.15 to 1:2.
[0019] In an embodiment, the molar ratio of the carboplatin and the
1,1-cyclobutane dicarboxylic acid in the combining step ranges from
1:3 to about 1:50.
[0020] In an embodiment, the molar ratio of the carboplatin and the
1,1-cyclobutane dicarboxylic acid in the combining step ranges from
1:5 to 1:10.
[0021] In an embodiment, the proportion of the weight of
carboplatin in grams and the volume of the solvent in mL in the
combining step ranges from about 1:2 to about 1:50.
[0022] In an embodiment, the proportion of the weight of the
carboplatin in grams and the volume of the solvent in mL in the
combining step ranges from about 1:3 to about 1:5.
[0023] In an embodiment, the dicycloplatin has an X-ray powder
diffraction pattern substantially as depicted in FIG. 2.
[0024] In an embodiment, the reaction temperature of the combining
step ranges from 0.degree. C. to 80.degree. C.
[0025] In an embodiment, the reaction temperature of the combining
step ranges from 10 to 25.degree. C.
[0026] In an embodiment, the solvent is an organic solvent selected
from the group consisting of: tetrahydrofuran (THF),
dichloromethane (DCM), isopropanol, ethanol, ethyl acetate (EtOAc),
dimethylformamide (DMF), 1,4-dixoane, acetone, toluene, isobutyl
acetate, isopropyl acetate, chloroform, 2-methoxyethanol, methyl
isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE),
1,2-dichloro ethane and a mixture thereof.
[0027] In an embodiment, the solvent is a mixture of water and an
organic solvent selected from the group consisting of: THF, DCM,
isopropanol, ethanol, EtOAc, DMF, 1,4-dixoane, acetone, toluene,
isobutyl acetate, isopropyl acetate, chloroform, 2-methoxyethanol,
MIBK, MTBE, 1,2-dichloro ethane and a mixture thereof.
[0028] In an embodiment, the reaction temperature of the combining
step ranges from 0.degree. C. to 80.degree. C.
[0029] In an embodiment, the reaction temperature of the combining
step ranges from 20 to 35.degree. C.
[0030] In some embodiments, the final product does not contain
carboplatin in an amount detectable with X-ray Powder Diffraction
(XRPD).
[0031] In some embodiments, the final product does not contain
carboplatin in an amount detectable with Differential Scanning
Calorimetry (DSC).
[0032] In some embodiments, the final product does not contain
carboplatin in an amount detectable with either XRPD or DSC.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] The following figures find a basis in Examples 7-9 as
described herein and are employed as merely illustrative of
particular embodiments of the present invention, and with no
intention of limiting the scope of the invention.
[0034] FIG. 1 shows a representative .sup.1H-NMR spectrum of the
product, where the product contains dicycloplatin and is dissolved
in DMSO-d.sub.6.
[0035] FIG. 2 shows a representative X-ray powder diffraction
(XRPD) pattern of the product, where the product contains
dicycloplatin (bottom pattern) and is compared to a standard XRPD
pattern of dicycloplatin (top pattern).
[0036] FIG. 3 shows a representative XRPD pattern of the product,
where the product contains dicycloplatin (bottom pattern) and is
compared to an XRPD pattern of carboplatin (top pattern).
[0037] FIG. 4 shows a representative differential scanning
calorimetric (DSC) thermogram of the product, where the product
contains dicycloplatin (bottom pattern) and is compared to a DSC
thermogram of 1,1-cyclobutane dicarboxylate (top pattern).
[0038] FIG. 5 shows a representative thermal gravimetric analysis
(TGA) thermogram of the product, where the product contains
dicycloplatin (bottom pattern).
[0039] FIG. 6 shows representative XRPD patterns of the product and
the patterns are compared to standard dicycloplatin and carboplatin
patterns.
[0040] FIG. 7 shows a representative XRPD pattern of the product,
where the product contains dicycloplatin and is compared to a
standard XRPD pattern of dicycloplatin and carboplatin.
DETAILED DESCRIPTION OF THE INVENTION
[0041] The following description of certain embodiment(s) is merely
exemplary in nature and is in no way intended to limit the
invention, its application, or uses. As used throughout, ranges are
used as shorthand for describing each and every value that is
within the range. Any value within the range can be selected as the
terminus of the range. In addition, all references cited herein are
hereby incorporated by reference in their entireties. In the event
of a conflict in a definition in the present disclosure and that of
a cited reference, the present disclosure controls.
[0042] The present invention provides a new process for preparing
dicycloplatin this is easy to operate, involves mild reactive
conditions and has a short reaction time. The new process is
reproducible and readily scaled up for industrial application. In
some embodiments, only water is used as a solvent (i.e., no organic
solvent). In some embodiments, only one organic solvent or a
mixture of organic solvents is used. In some embodiments, a mixture
of organic solvent and water is used.
[0043] In an exemplary embodiment, the present invention provides a
process for producing dicycloplatin, comprising: suspending
carboplatin in corresponding proportion of 1,1-cyclobutane
dicarboxylic acid and a solvent to form a suspension; stirring the
suspension to form precipitating solids; and drying the solids,
wherein the solids comprise dicycloplatin of formula I and does not
contain carboplatin.
[0044] In some embodiments, the process further comprises cooling
the precipitating solids. In some embodiments, the process further
comprises filtering the precipitating solids. In some embodiments,
the process further comprises re-crystallizing the solids.
[0045] In some embodiments, the solvent is water.
[0046] In some embodiments, the molar ratio of carboplatin and
1,1-cyclobutane dicarboxylic acid is lower than 1:1. In some
embodiments, the molar ratio of carboplatin and 1,1-cyclobutane
dicarboxylic acid is lower than 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4,
1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5,
1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40,
1:45, or 1:50.
[0047] In some specific embodiments, the molar ratio of carboplatin
and 1,1-cyclobutane dicarboxylic acid ranges from about 1:1.15 to
about 1:2, from about 1:1.15 to about 1:3, from about 1:1.15 to
about 1:4, from about 1:1.15 to about 1:5, from about 1:1.15 to
about 1:6, from about 1:1.15 to about 1:7, from about 1:1.15 to
about 1:8, from about 1:1.15 to about 1:9, from about 1:1.15 to
about 1:10, from about 1:1.15 to about 1:15, from about 1:1.15 to
about 1:20, from about 1:1.15 to about 1:25, from about 1:1.15 to
about 1:30, from about 1:1.15 to about 1:40, from about 1:1.15 to
about 1:50.
[0048] In some embodiments, the proportion of carboplatin (weight,
g) and solvent (volume, mL) ranges from about 1:2 to about 1:50. In
some specific embodiments, the proportion of carboplatin (weight,
g) and solvent (volume, mL) ranges from about 1:3 to about 1:5.
[0049] In some embodiments, the final dicycloplatin product does
not contain carboplatin in an amount of more than 5%, 3%, 1%, 0.5%,
0.1%, 0.05%, 0.01%, 0.005%, or 0.001% of the final product by
weight.
[0050] In some embodiments, the final dicycloplatin product is at
least 95%, 96%, 97%, 98%, 99% or 99.9% pure.
[0051] The reactions are typically carried out under mild
temperature. However, the reactions can also be processed under
high temperatures or low temperatures. The reactions are typically
carried out under normal pressure. However, the reactions can also
be processed under increased pressure or decreased pressure.
[0052] In some embodiments, organic solvents may be used as the
solvent to produce the desired products. Exemplary organic solvents
include, but are not limited to, THF, DCM, isopropanol, ethanol,
EtOAc, DMF, 1,4-dixoane, acetone, toluene, isobutyl acetate,
isopropyl acetate, chloroform, 2-methoxyethanol, MIBK, MTBE,
1,2-dichloro ethane and mixtures of two or more solvents, or
mixtures of water and organic solvents. In some specific
embodiments, the organic solvent is DCM.
[0053] The following non-limiting examples further illustrate
certain aspects of the present invention.
EXAMPLES
X-Ray Powder Diffraction (XRPD)
[0054] Analytical Instrument: Panalytical Empyrean. The X-ray
powder diffraction was conducted by mounting a sample of the
crystalline material on a Si single crystal low-background holder
and spreading out the sample into a thin layer with the aid of a
microscope slide. The 2-theta (2-.theta.) position was calibrated
against a Panalytical 640 Si powder standard. The sample was
irradiated with X-rays generated by a copper long-fine focus tube
operated at 45 kV and 40 mA with a wavelength of K.alpha.1=1.540589
angstroms and K.alpha.2=1.544426 angstroms (K.alpha.2/K.alpha.1
intensity ratio is 0.50). The collimated X-ray source was passed
through a programmed divergence slit set at 10 mm and the reflected
radiation directed through a 5.5 mm anti-scatter slit. The sample
was exposed for 16.3 seconds per 0.013.degree. 2-theta increment
(continuous scan mode) over the range of 3 degrees to 40 degrees
2-theta in theta-theta mode. The running time was 3 minutes and 57
seconds. The instrument was equipped with a RTMS detector
(X'Celerator). Control and data capture was by means of a Dell
Optiplex 780 XP operating with data collector software.
[0055] It is known in the art that the relative intensities of
peaks can be affected by, for example, grains above 30 microns in
size and that non-unitary aspect ratios may affect analysis of
samples. It is also known that the position of reflections can be
affected by the precise height at which the sample sits in the
diffractometer and the zero calibration of the diffractometer.
[0056] The surface planarity of the sample may also have a limited
effect. As a result, the diffraction pattern data presented are not
intended to be limited to the absolute values.
Differential Scanning Calorimetry (DSC)
[0057] DSC was used as a thermoanalytical method to measure the
difference in the amount of heat required to increase the
temperature of a sample and reference was measured as a function of
temperature. The general process of DSC is known and the specific
instruments and conditions employed in the described Examples were
as follows:
[0058] Analytical Instrument: TA Instruments Q2000 DSC;
[0059] Heating rate: 10.degree. C. per minute; and
[0060] Purge gas: nitrogen.
Thermal Gravimetric Analysis (TGA)
[0061] TGA was used to measure changes in physical and chemical
properties of samples as a function of increasing temperature (with
a constant heating rate), or as a function of time (with constant
temperature and/or constant mass loss). The general process of TGA
is known and the specific instruments and conditions in the
described Examples were as follows:
[0062] Analytical Instrument: TA Instruments Q5000 TGA;
[0063] Heating rate: 10.degree. C. per minute; and
[0064] Purge gas: nitrogen.
.sup.1H Nuclear Magnetic Resonance (.sup.1H NMR)
[0065] The general process of .sup.1H NMR spectroscopy is known and
the specific instruments and conditions employed in the described
Examples were as follows: solution NMR was collected on a Bruker
400M NMR Spectrometer using DMSO-d6.
Example 1
Preparation Procedures for Dicycloplatin
[0066] 1) Charged 5.0 g of carboplatin (13.47 mmol) and 2.232 g of
1,1-cyclobutane dicarboxylic acid (15.50 mmol) into a 20-mL glass
vial. [0067] 2) Added 12.5 mL of deionized water into the same vial
and stirred the mixture at RT (room temperature) to form uniform
suspension while keeping the vial away from light. [0068] 3) Cooled
the mixture to 5.degree. C. at a rate of 0.33.degree. C./min and
aged at 5.degree. C. for 20 hours to form a precipitation cake.
[0069] 4) Vacuum filtered and washed the cake with 5 mL of
deionized water, and then vacuum dried the wet cake. [0070] 5)
Collected the solids from the dried cake and measured the amount of
dicycloplatin. [0071] 6) 6.49 g dicycloplatin was obtained with an
overall yield of 93.2%.
[0072] The product was analyzed by XRPD, DSC, TGA and .sup.1H
NMR.
[0073] .sup.1H NMR results: (400 MHz, DMSO-d6) .delta. 12.63 (s,
2H), 4.09 (s, 6H), 2.67 (t, J=7.9 Hz, 4H), 2.37 (t, J=8.0 Hz, 4H),
1.95-1.76 (m, 2H), 1.73-1.55 (m, 2H).
[0074] The XRPD data are listed in Table 1.
TABLE-US-00001 TABLE 1 2-theta d-spacing intensity % 7.5 11.8 100.0
15.0 5.9 46.7 16.4 5.4 6.0 16.8 5.3 12.7 18.5 4.8 9.8 20.8 4.3 8.6
21.1 4.2 5.1 21.5 4.1 7.7 22.0 4.0 10.7 22.8 3.9 15.6 24.0 3.7 16.6
26.5 3.4 5.4 29.7 3.0 5.5 30.5 2.9 6.5 33.2 2.7 4.6
Example 2
Preparation Procedures for Dicycloplatin
[0075] 1) Charged 1.0 g of carboplatin (2.69 mmol) and 776.4 mg of
1,1-cyclobutane dicarboxylic acid (5.39 mmol) into a 20-mL glass
vial. [0076] 2) Added 5 mL of deionized water into the same vial
and stirred the suspension at RT for 6 hours while keeping the vial
away from light to form a precipitation cake. [0077] 3) Vacuum
filtered and washed the cake with 2.8 mL of deionized water
rapidly, and then vacuum dried the wet cake. [0078] 4) Collected
the solids from the dried cake and measured the amount of
dicycloplatin.
[0079] The product was analyzed by XRPD, DSC, TGA and .sup.1H
NMR.
[0080] .sup.1H NMR results: (400 MHz, DMSO-d6) .delta. 12.65 (s,
2H), 4.09 (s, 6H), 2.67 (t, J=7.9 Hz, 4H), 2.37 (t, J=8.0 Hz, 4H),
1.92-1.77 (m, 2H), 1.72-1.57 (m, 2H).
[0081] The XRPD data are listed in Table 2.
TABLE-US-00002 TABLE 2 2-theta d-spacing intensity % 7.6 11.7 100.0
15.1 5.9 66.3 16.5 5.4 11.8 16.8 5.3 23.6 18.5 4.8 17.1 20.8 4.3
15.3 21.5 4.1 12.1 22.1 4.0 17.8 22.8 3.9 33.8 24.0 3.7 34.2 26.5
3.4 12.3 29.8 3.0 11.6 30.6 2.9 18.6 31.5 2.8 11.7 33.3 2.7
11.8
Example 3
Preparation Procedures for Dicycloplatin
[0082] 1) Charged 5.0 g of carboplatin (13.47 mmol) and 2.523 g of
1,1-cyclobutane dicarboxylic acid (17.52 mmol) into a 100-mL glass
vial. [0083] 2) Added 25 mL of deionized water into the same vial
and stirred the suspension at RT for 5 hours while keeping the vial
away from light to form a precipitation cake. [0084] 3) Vacuum
filtered and washed the cake with 5 mL of deionized water rapidly,
and then vacuum dried the wet cake. [0085] 4) Collected the solids
from the dried cake and measured the amount of dicycloplatin.
[0086] 5) 5.88 g of dicycloplatin was obtained with an overall
yield of 84.2%.
[0087] The product was analyzed by XRPD, DSC, TGA and .sup.1H
NMR.
[0088] .sup.1H NMR results: (400 MHz, DMSO-d6) .delta. 12.63 (s,
2H), 4.09 (s, 6H), 2.67 (t, J=7.9 Hz, 4H), 2.37 (t, J=8.0 Hz, 4H),
1.90-1.80 (m, 2H), 1.70-1.59 (m, 2H).
[0089] The XRPD data are listed in Table 3.
TABLE-US-00003 TABLE 3 2-theta d-spacing intensity % 7.5 11.8 100.0
15.0 5.9 90.9 16.4 5.4 13.8 16.8 5.3 24.2 18.5 4.8 22.9 21.1 4.2
10.8 22.0 4.0 11.4 22.8 3.9 30.9 24.0 3.7 37.4 26.5 3.4 6.5 29.7
3.0 8.8 30.5 2.9 16.9 31.4 2.8 8.4 31.6 2.8 8.0 33.2 2.7 10.6
Example 4
Preparation Procedures for Dicycloplatin
[0090] 1) Weighed 5.0 g of carboplatin (13.47 mmol) and 2.523 g of
1,1-cyclobutane dicarboxylic acid (17.52 mmol) into a 100-mL glass
vial. [0091] 2) Added 25 mL of deionized water into the same vial
and stirred the mixture at RT to form a uniform suspension while
keeping the vial away from light. [0092] 3) Cooled the mixture to
5.degree. C. at a rate of 0.33.degree. C./min and aged at 5.degree.
C. for 19 hours to form a precipitation cake. [0093] 4) Vacuum
filtered and dried the wet cake. [0094] 5) Collected the solids
from the dried cake and measured the amount of dicycloplatin.
[0095] 6) 6.11 g of dicycloplatin was obtained with an overall
yield of 87.1%.
[0096] The product was analyzed by XRPD, DSC, TGA and .sup.1H
NMR.
[0097] .sup.1H NMR results: (400 MHz, DMSO-d6) .delta. 12.65 (s,
2H), 4.09 (s, 6H), 2.67 (t, J=7.9 Hz, 4H), 2.37 (t, J=8.0 Hz, 4H),
1.94-1.77 (m, 2H), 1.74-1.51 (m, 2H).
[0098] The XRPD data are listed in Table 4.
TABLE-US-00004 TABLE 4 2-theta d-spacing intensity % 7.6 11.7 100.0
15.1 5.9 20.6 16.4 5.4 2.9 16.8 5.3 8.9 18.5 4.8 4.7 20.3 4.4 2.8
20.8 4.3 4.0 21.5 4.1 2.5 22.1 4.0 4.5 22.8 3.9 11.4 24.0 3.7 9.6
26.5 3.4 3.0 29.8 3.0 2.4 30.6 2.9 5.1 31.5 2.8 2.7
Example 5
Preparation Procedures for Dicycloplatin
[0099] 1) Added 60.08 g of 1,1-cyclobutane dicarboxylic acid
(417.22 mmol) and 593 mL of deionized water into a 1-L shaded
crystallizer. [0100] 2) Charged 118.6 g of carboplatin (319.46
mmol) into the same crystallizer and stirred the mixture for 6
hours at RT. [0101] 3) Cooled the mixture to 5.degree. C. at a rate
of 0.33.degree. C./min and aged at 5.degree. C. for 19 hours to
form a precipitation cake. [0102] 4) Vacuum filtered and washed the
cake with 120 mL of deionized water, and then vacuum dried the wet
cake. [0103] 5) Collected the solids from the dried cake and
measured the amount of dicycloplatin. [0104] 6) 148.52 g of
dicycloplatin was obtained with overall yield of 90.2%.
[0105] The product was analyzed by XRPD, DSC, TGA and .sup.1H
NMR.
[0106] .sup.1H NMR results: (400 MHz, DMSO-d6) .delta. 12.63 (s,
2H), 4.09 (s, 6H), 2.67 (t, J=7.9 Hz, 4H), 2.37 (t, J=8.0 Hz, 4H),
1.95-1.77 (m, 2H), 1.73-1.55 (m, 2H).
[0107] The XRPD data are listed in Table 5.
TABLE-US-00005 TABLE 5 2-theta d-spacing intensity % 7.5 11.8 100.0
15.0 5.9 23.5 16.4 5.4 3.1 16.8 5.3 8.3 18.5 4.8 4.7 20.3 4.4 2.8
21.1 4.2 2.4 22.0 4.0 1.5 22.8 3.9 17.4 24.0 3.7 9.5 26.5 3.4 1.0
27.7 3.2 2.4 30.6 2.9 7.3 31.4 2.8 3.3 39.2 2.3 2.5
Example 6
Preparation Procedures for Dicycloplatin
[0108] 1) Added 2.239 g of 1,1-cyclobutane dicarboxylic acid (15.55
mmol) and 15 mL of deionized water into a 20-mL glass vial. [0109]
2) Charged 5.0 g of carboplatin (13.47 mmol) into the same vial and
stirred the mixture at RT. [0110] 3) Cooled the mixture to
5.degree. C. at a rate of 0.33.degree. C./min and aged at 5.degree.
C. for 19 hours to form a precipitation cake. [0111] 4) Vacuum
filtered and washed the cake with 5 mL of deionized water, and then
vacuum dried the wet cake. [0112] 5) Collected the solids and
measured the amount of cycloplatin. [0113] 6) 6.40 g of
dicycloplatin was obtained with overall yield of 92.2%.
[0114] The product was analyzed by XRPD, DSC, TGA and .sup.1H
NMR.
[0115] .sup.1H NMR results: (400 MHz, DMSO-d6) .delta. 12.63 (s,
2H), 4.09 (s, 6H), 2.67 (t, J=7.9 Hz, 4H), 2.37 (t, J=8.0 Hz, 4H),
1.93-1.75 (m, 2H), 1.74-1.51 (m, 2H).
[0116] The XRPD data are listed in Table 6.
TABLE-US-00006 TABLE 6 2-theta d-spacing intensity % 7.6 11.7 100.0
15.2 5.8 30.9 16.5 5.4 3.7 16.9 5.2 9.8 18.6 4.8 5.9 20.4 4.3 3.6
20.9 4.3 5.5 22.1 4.0 5.6 22.9 3.9 21.0 24.1 3.7 12.4 26.6 3.3 3.0
27.8 3.2 3.4 30.7 2.9 8.7 31.6 2.8 4.5 39.3 2.3 3.6
Representative Results from Examples 1-6
[0117] The .sup.1H NMR spectra from Examples 1-6 are highly
similar. FIG. 1 shows a representative .sup.1H NMR spectrum of a
product obtained in Example 1. The .sup.1H NMR spectrum indicates
the product contained dicycloplatin and that the molar ratio of the
two components (1,1-cyclobutane dicarboxylic acid and carboplatin)
in dicycloplatin is 1:1.
[0118] The X-ray powder diffraction (XRPD) patterns from Examples
1-6 are also highly similar. FIG. 2 shows the representative XRPD
pattern of a product obtained in Examples 1 and 2 compared to a
standard XRPD pattern of dicycloplatin (based on Yang et al.,
Science China Chemistry, 40(5): 485-491 (2010)), indicating that
the sample was dicycloplatin.
[0119] FIG. 3 shows a representative XRPD pattern of a product
obtained in Example 5 compared to a standard XRPD pattern of
carboplatin, indicating that there was no traceable carboplatin in
the sample obtained in the above Examples.
[0120] The differential scanning calorimetry (DSC) thermograms from
the Examples 1-6 are also highly similar. FIG. 4 shows a
representative DSC thermogram of dicycloplatin obtained in Example
5, showing that there was no evidence of 1,1-cyclobutane
dicarboxylic acid (i.e., no signal of the melting point of
1,1-cyclobutane dicarboxylic at 159.7.degree. C.) present in the
products obtained in the above Examples.
[0121] The representative thermal gravimetric analysis (TGA)
thermograms from Examples 1-6 arc also highly similar. FIG. 5 shows
a representative TGA thermogram of a product obtained in Example 5.
The dicycloplatin has a TGA thermogram comprising about 0.5% weight
loss up to 150.degree. C.
Example 7
Preparation Procedures for Dicycloplatin
[0122] 1) Dissolved 50.0 mg of carboplatin (135 .mu.mol) in 2.8 mL
of water in a 3-mL glass vial at RT. [0123] 2) Added 19.4 mg of
1,1-cyclobutane dicarboxylic acid (135 .mu.mol) into the same vial.
[0124] 3) Stirred the suspension at RT to obtain a clear solution.
[0125] 4) Transferred the clear solution to a 25-mL round-bottom
flask and rotary evaporated at a temperature between 50.degree. C.
and 55.degree. C. to obtain white crystal solid. [0126] 5)
Air-dried the solid to obtain a product.
[0127] The product was analyzed by XRPD, DSC and TGA.
[0128] The XRPD data are listed in Table 7.
TABLE-US-00007 TABLE 7 2-theta d-spacing intensity % 7.6 11.6 100.0
15.1 5.9 82.9 16.5 5.4 23.4 16.9 5.3 13.9 18.6 4.8 44.9 21.2 4.2
15.0 22.9 3.9 16.5 24.1 3.7 33.2 24.1 3.7 15.8 24.8 3.6 7.8 30.6
2.9 10.3 31.7 2.8 11.9 33.3 2.7 11.7 33.4 2.7 6.2 37.6 2.4 9.2
Example 8
Preparation Procedures for Dicycloplatin
[0129] 1) Dissolved 15.1 mg of carboplatin (41 .mu.mol) and 5.9 mg
of 1,1-cyclobutane dicarboxylic acid (41 .mu.mol) in 1.0 mL of
water in a 3-mL glass vial. [0130] 2) After filtering by 0.45 .mu.m
filter membrane, the filtrate was transferred to a 4-mL glass.
Covered the vial with aluminum-foil paper to keep solution away
from light and evaporated the solution freely at RT.
[0131] The product was analyzed by XRPD, DSC and TGA.
[0132] The XRPD data are listed in Table 8.
TABLE-US-00008 TABLE 8 2-theta d-spacing intensity % 7.5 11.8 100.0
15.1 5.9 41.3 16.8 5.3 18.0 18.5 4.8 11.4 20.8 4.3 11.1 22.0 4.0
11.2 22.8 3.9 34.8 24.0 3.7 28.9 26.5 3.4 10.5 27.6 3.2 8.4 30.6
2.9 19.4 31.5 2.8 8.0
Example 9
Preparation Procedures for Dicycloplatin
[0133] 1) Charged 49.7 mg of carboplatin (134 .mu.mol) in 2.8 mL of
water in a 3-mL of vial and stirred the suspension to obtain a
clear solution at RT. [0134] 2) Added 19.4 mg of 1,1-cyclobutane
dicarboxylic acid (135 .mu.mol) into the same vial. [0135] 3)
Stirred the solution in a vial wrapped with aluminum-foil at RT.
[0136] 4) Solid was observed after slurry for about 15 min and
isolated by centrifuging.
[0137] The product was analyzed by XRPD, DSC and TGA.
[0138] The XRPD data are listed in Table 9.
TABLE-US-00009 TABLE 9 2-theta d-spacing intensity % 7.6 11.6 23.4
14.7 6.0 6.1 15.0 5.9 14.2 15.2 5.8 100.0 15.4 5.8 4.6 16.5 5.4 9.0
22.9 3.9 5.9 24.1 3.7 9.2 24.2 3.7 4.4 29.8 3.0 11.3 29.9 3.0 6.0
31.7 2.8 13.7 31.8 2.8 7.3 33.4 2.7 6.7 33.5 2.7 4.0
Test According to a Reported Process.
[0139] Examples 7-9 represent experiments conducted according to
the reported process in U.S. Pat. No. 6,699,901. In brief,
carboplatin was dissolved in water and cyclobutane dicarboxylic
acid was added to the solution while stirring. The molar ratio of
the carboplatin and the cyclobutane dicarboxylic acid was 1:1. The
mixture was completely dissolved and the solution was evaporated to
produce a dried product. The XRPD pattern results for the product
are shown in FIG. 6.
[0140] The XRPD results arc shown in FIG. 6. On scales of or higher
than approximately 250 mg, the final product contained not only
dicycloplatin, but also a significant amount of carboplatin,
demonstrated by the XRPD patterns in FIG. 6, where the product XRPD
patterns illustrate similar peaks compared to the standard
carboplatin XRPD. Moreover, carboplatin proved difficult to remove,
rendering the entire product unusable.
[0141] The high level of carboplatin present in the final product
may be due to several reasons. Using a 1:1 molar ratio may be one
reason that carboplatin are still present.
[0142] Since evaporation was required in the reported process,
dicycloplatin was degraded in the product because it is sensitive
to high temperature.
[0143] Moreover, in additional polymorph studies of dicycloplatin,
it was recognized that the use of shorter aliphatic alcohols (as
reported in U.S. Pat. No. 6,699,901) such as methanol, ethanol,
isopropanol and butanol led to a significant amount of carboplatin
being left in the product because of disproportionation. In
addition, the water solubility of dicycloplatin is limited (40
mg/mL at room temperature), and it was observed that a slurry of
dicycloplatin in hot water caused partial hydrolysis). Thus,
recrystallization in water was not efficient and was difficult to
scale up.
[0144] As indicated by the results of the current Examples, the
reported process was not robust and was difficult to scale up.
Example 10
Preparation of Dicycloplatin Using Dichloromethane (DCM) as a
Solvent
[0145] 1) Charged 500 mg of carboplatin (1.347 mmol) in 20 mL of
DCM in a 50-mL of flask and stirred the suspension to obtain a
clear solution at RT. [0146] 2) Added 582 mg of 1,1-cyclobutane
dicarboxylic acid (4.038 mmol) into the same flask. [0147] 3)
Stirred the solution in vial wrapped with aluminum-foil at
20-35.degree. C. [0148] 4) Stirred over 12 hours and then filtered,
washed with DSM.
[0149] The product obtained by this example was analyzed by XRPD,
DSC and TGA. FIG. 7 shows a representative XRPD pattern for the
product obtained according to the process of Example 10. The
results indicate that the product contained dicycloplatin, with
less than traceable amounts of carboplatin.
Example 11
Preparation of Dicycloplatin Using Different Solvents
[0150] Different solvents, including organic solvents, were used
for the preparation of dicycloplatin. A summary of the products is
provided in Table 10.
TABLE-US-00010 TABLE 10 mol ratio (A/B) solvent (v/v) 10:1 2:1 1:1
1:2 1:5 1:10 EtOH/H.sub.2O (19:1) A A A A + C (A + B + C)
ACN/H.sub.2O (9:1) A A A A (A + B + C) Acetone/H.sub.2O (19:1) A A
A A (B + C)* 1,4-dioxane/H.sub.2O A A A A (B + C)* (9:1) H.sub.2O A
A (A + B + C) (B + C)* (B + C)* (B + C)* DCM A A A (A + B + C) (B +
C)* (B + C)* Isopropanol A A A A + C (A + B + C)
Isopropanol/H.sub.2O (A + B + C) (3:1) Toluene (B + C)* THF (A + B
+ C) Acetone (B + C)* EtOAc A A A A + B (B + C)* (1) A:
carboplatin; B: 1,1-cyclobutane carboxylic acid; C: dicycloplatin
(2) *indicates that substantially pure dicycloplatin was obtained
in a significant quantity after further processing such as
filtering, washing and drying.
[0151] Table 10 shows the initial product after precipitation.
1,1-cyclobutane carboxylic acid can be removed easily but
carboplatin cannot be removed. Therefore, to obtain pure
dicycloplatin, co-precipitation of carboplatin should be
prevented.
* * * * *