Patent Application
20080207904
The present invention is directed to crystalline Imatinib base, Imatinib free of desmethyl imatinib and imatinib mesylate free of desmethyl Imatinib mesylate, respectively, processes for preparation thereof and pharmaceutical compositions thereof.
Imatinib mesylate, 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-pyrinin-3-yl)pyrimidin-2-yloamino]phenyl]benzamide mesylate, a compound having the following chemical structure,
is a protein-tyrosine kinase inhibitor, especially useful in the treatment of various types of cancer and can also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus, imatinib mesylate can be used also for the treatment of non-malignant diseases. Imatinib mesylate is usually administered orally in the form of a suitable salt, e.g., in the form of imatinib mesylate, and is marketed by Novartis under the trade name Gleevec® in the USA.
Imatinib base is the key intermediate for preparing imatinib salts such as imatinib mesylate. U.S. Pat. No. 5,521,184, International Application Nos. WO 03/066613, 04/108699, 04/074502, 06/071130 and US application Nos. 04/0248918, 06/0149061, 06/0223817 describe the synthesis of Imatinib-base, its isolation and its purification by column chromatography or by crystallization from different solvents.
The isolation is performed by precipitating the base from mixtures of n-butanol and butylacetate, ethylacetate, water, or mixtures of water and organic solvent. The isolated crystalline form of imatinib base described in the above references is characterized by main PXRD peaks at: 6.0, 17.2, 18.1, 18.7, 19.8, 20.9, 23.8, 24.3, and 25.2±0.2 degrees two-theta, denominated form I. Specifically such isolation as described includes “mixing Imatinib base and n-butanol, heating the mixture to 91° C. until a clear solution is obtained. The solution is cooled to room temperature and the resulting crystals are washed with 2 ml of cold n-butanol, filtered and dried under reduced pressure.” The same process is also reported for the following solvents: toluene, cyclohexane, chloroform, dichloromethane, acetonitrile, methanol, methyl-ethyl-ketone, methyl-iso-butyl-ketone, iso-propanol and ethylacetate; wherein the temperature for achieving a clear solution is different. Further, the column chromatography is performed by using methanol or its mixtures with chloroform. When purified by crystallization, the solvent of choice can be n-butanol, toluene and others.
The present invention relates to the solid state physical properties of Imatinib base. These properties can be influenced by controlling the conditions under which imatinib base is obtained in solid form. Solid state physical properties include, for example, the flow-ability of the milled solid. Flow-ability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography (PXRD), solid state 13C NMR spectrometry and infrared spectroscopy.
One of the most important physical properties of a pharmaceutical compound, which can form polymorphs, is its solubility in aqueous solution, particularly the solubility in gastric juices of a patient. Other important properties relate to the ease of processing the form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.
Further, the base can then be converted to the mesylate salt, which is isolated by precipitation from the reaction mixture consisting of the base, methansulfonic acid and a solvent as described in International Application Nos. WO 99/03854, WO 2005/077933, WO 2005/095379, WO 2004/106326, WO 2006/054314, WO 2006/024863, WO 2006/048890, US2006/0030568, WO 2007/023182, and U.S. Pat. No. 6,894,051.
Like any synthetic compound, Imatinib mesylate can contain extraneous compounds or impurities, such as desmethyl imatinib mesylate. Des-methyl imatinib mesylate and process for its preparation are disclosed in U.S. Pat. No. 7,081,532.
Impurities in Imatinib mesylate, or any active pharmaceutical ingredient (“API”), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The purity of an API produced in a manufacturing process is critical for commercialization. The U.S. Food and Drug Administration (“FDA”) requires that process impurities be maintained below set limits. For example, in its ICH Q7A guidance for API manufacturers, the FDA specifies the quality of raw materials that may be used, as well as acceptable process conditions, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction. See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version (Nov. 10, 2000).
The product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product. At certain stages during processing of an API, it must be analyzed for purity, typically, by high performance liquid chromatography (“HPLC”) or thin-layer chromatography (“TLC”), to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The FDA requires that an API is as free of impurities as possible, so that it is as safe as possible for clinical use. For example, the FDA recommends that the amounts of some impurities be limited to less than 0.1 percent. See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version (Nov. 10, 2000).
Generally, side products, by-products, and adjunct reagents (collectively “impurities”) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. See Strobel, H. A., et al., C
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
The discovery of new polymorphic forms of Imatinib base provides a new opportunity to improve the performance of the synthesis of the active pharmaceutical ingredient (API), Imatinib mesylate, by producing crystalline forms of Imatinib base having improved characteristics, such as flowability, and solubility. Thus, there is a need in the art for polymorphic forms of Imatinib base. In addition, providing Imatinib free of des-methyl Imatinib, and Imatinib mesylate free of des-methyl Imatinib mesylate, and means for preparation thereof is beneficial.
In one embodiment, the present invention encompasses crystalline Imatinib base characterized by at least one data selected from the group consisting of: a powder XRD pattern having any five peaks selected from the list consisting of peaks at about: 6.4, 8.1, 10.2, 12.8, 16.1, 19.4, 20.4, 21.7, 22.1, 25.8 and 26.7±0.2 degrees two-theta; a solid-state 13C NMR spectrum with signals at about 159.6, 146.7, 136.8 and 132.4±0.2 ppm; a solid-state 13C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 51.2, 38.3, 28.4 and 24.0±0.1 ppm, and combinations thereof.
In another embodiment, the present invention encompasses crystalline Imatinib base characterized by at least one data selected from the group consisting of: a powder XRD depicted in
In yet another embodiment, the present invention encompasses a process for preparing the above crystalline Imatinib base comprising crystallizing imatinib base from a mixture containing pyridine.
In one embodiment, the present invention encompasses amorphous imatinib base. Amorphous imatinib base has a large surface area and a faster dissolution rate than the crystalline imatinib base. These properties of amorphous imatinib base are advantageous in a subsequent reaction with methanesulfonic acid to prepare imatinib mesylate.
In another embodiment, the present invention encompasses amorphous Imatinib base prepared by a process comprising lyophilizing a solution of imatinib base in 1,4-dioxane.
In yet another embodiment, the present invention encompasses a process for preparing Imatinib salt comprising preparing any one of the forms of imatinib base of the present invention, and converting them to Imatinib salt.
In one embodiment, the present invention encompasses the use of any one of the forms of imatinib base of the present invention for the preparation of Imatinib salt.
In another embodiment, the present invention encompasses Imatinib of the following formula
having less than about 0.09% area by HPLC of desmethyl-imatinib of the following formula.
In one embodiment, the present invention encompasses a process for preparing Imatinib base having less than about 0.09% area by HPLC of desmethyl-imatinib comprising measuring the level of the desmethyl impurity of formula II
in at least one batch of the compound of formula I
selecting a batch of the compound of formula I having less than about 0.15% area by HPLC of the desmethyl impurity of formula II; and preparing imatinib base comprising the selected batch of the compound of formula I.
In one embodiment, the present invention encompasses a process for preparing Imatinib having less than about 0.09% area by HPLC of desmethyl-imatinib comprising: a) providing the compound of formula I
having less than about 0.15% area by HPLC of the desmethyl compound of formula II;
b) reacting it with the amine of formula III,
to obtain Imatinib having less than about 0.09% area by HPLC of desmethyl imatinib, and optionally
c) crystallizing imatinib base to obtain crystalline Imatinib having less than about 0.09% area by HPLC of desmethyl imatinib.
In another embodiment, the present invention encompasses a process for preparing Imatinib mesylate having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate comprising measuring the level of the desmethyl-imatinib in at least one batch of imatinib, selecting a batch of imatinib having less than about 0.09% area by HPLC of desmethyl-imatinib; and preparing imatinib mesylate comprising the selected batch of imatinib base.
In yet another embodiment, the present invention encompasses Imatinib mesylate of the following formula
having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate of the following formula.
In another embodiment, the present invention encompasses a pharmaceutical composition comprising imatinib mesylate having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate and at least one pharmaceutically acceptable excipient.
In yet another embodiment, the present invention encompasses a process for preparing the pharmaceutical composition, comprising combining imatinib mesylate having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate with a pharmaceutically acceptable excipient.
In one embodiment, the present invention encompasses the use of imatinib mesylate having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate in the manufacture of a pharmaceutical composition for the treatment of various types of cancer, atherosclerosis, thrombosis, restenosis, or fibrosis.
In another embodiment, the present invention encompasses the des-methyl compound of formula IV
In yet another embodiment, the present invention encompasses a process for preparing the des-methyl compound of formula IV comprising reacting des-methyl imatinib of the following formula
and the compound of formula V,
wherein X is a leaving group, HA is an acid, and n is 0, 1 or 2.
In one embodiment, the present invention encompasses a process of determining the presence of the des-methyl compound of formula IV in Imatinib by a process comprising carrying out HPLC or TLC with the des-methyl compound of formula IV as a reference standard.
In another embodiment, the present invention encompasses a process of determining the amount of the des-methyl compound of formula IV in a sample comprising the des-methyl compound of formula IV and imatinib by a process comprising carrying out HPLC with the des-methyl compound of formula IV as a reference standard.
As used herein, the term “Imatinib” refers to Imatinib base of the following formula.
As used herein, the term “chemical shift difference” refers to the difference in chemical shifts between a reference signal and another signal in the same solid-state 13C NMR spectrum. In the present patent application the chemical shift differences were calculated by subtracting the chemical shift value of the signal exhibiting the lowest chemical shift (reference signal) in the solid-state 13C NMR spectrum in the range of 90 to 180 ppm from chemical shift values of another (observed) signals in the same solid-state NMR spectrum in the range of 90 to 180 ppm. These chemical shift differences are to provide a measurement for a substance, for example imatinib, of the present invention compensating for a phenomenon in NMR spectroscopy wherein, depending on the instrumentation, temperature, and calibration method used, a shift in the solid-state NMR “fingerprint” is observed. This shift in the solid-state NMR “fingerprint”, having signals at certain positions, is such that although the individual chemical shifts of signals have altered, the difference between chemical shifts of each signal and another is retained.
The present invention encompasses crystalline Imatinib base. This crystal form can be characterized by at least one data selected from the group consisting of: a powder XRD pattern having any five peaks selected from the list consisting of peaks at about: 6.4, 8.1, 10.2, 12.8, 16.1, 19.4, 20.4, 21.7, 22.1, 25.8 and 26.7±0.2 degrees two-theta; a solid-state 13C NMR spectrum with signals at about 159.6, 146.7, 136.8 and 132.4±0.2 ppm; a solid-state 13C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 51.2, 38.3, 28.4 and 24.0±0.1 ppm. The signal exhibiting the lowest chemical shift in the chemical shift range of 100 to 180 ppm is, typically, at about 108.4±0.2 ppm.
This crystalline form can also be characterized by at least one data selected from the group consisting of: a powder XRD depicted in
This crystalline Imatinib base can be further characterized by at least one data selected from the group consisting of: a powder XRD pattern having peaks at about 8.1, 10.2, 12.8, 16.1, and 19.4±0.2 degrees two-theta; a powder XRD pattern having peaks at about 6.4, 8.1, 10.2, 19.4, 20.4 and 25.8±0.2 degrees two-theta; a powder XRD pattern with peaks at about 17.3, 20.4, 21.1, and 25.8±0.2 degrees two-theta; a powder XRD pattern with peaks at about 6.4, 21.7, 22.1 and 26.7±0.2 degrees two-theta; a solid-state 13C NMR spectrum with signals at about 125.8 and 108.4±0.2 ppm; a DSC curve having 2 peaks, the first peak is an endothermic peak at 97.6° C. due to desolvation of the solvate, the second is an endothermic peak at 210.5° C. due to melting of desolvated product; and a DSC curve depicted in
The crystalline imatinib base of the present invention is a pyridine solvate of imatinib base, preferably, a hemi-pyridine solvate. The content of pyridine is of about 7% as measured by Gas Chromatography (GC) (area percent).
The said crystalline imatinib base has less than about 20% of crystalline form I of Imatinib base, preferably, less than about 10% of crystalline form I, most preferably, less than about 5% of crystalline form I, as measured either by PXRD or solid-state 13C NMR. Typically, the content of crystalline form I of imatinib base in the above form is measured by % by weight.
The content of crystalline form I can be measured, for example, by PXRD or by solid state 13C NMR. When measured by PXRD, the content of crystalline form I can be determined by using peaks of crystalline form I that are selected from the following list of peaks: 6.0, 9.5, 14.0, 17.1, 18.1, 18.6, 24.2 and 29.1±0.2 degrees two theta.
When measured by solid-state 13C NMR, the content of crystalline form I can determined by using signals selected from the following list of signals at about: 105.4, 122.2, 124.2, 129.1, 140.0, 142.4, 148.5, 150.7, 158.4 and 162.2 ppm±0.2 ppm.
The said crystalline Imatinib base may be prepared according to the process disclosed in Co-application Ser. No. 11/978,227, filed Oct. 26, 2007, incorporated herein by reference. The process comprises reacting the amine of formula III,
with a 4-[(4-methyl-1-piperazinyl)methyl]benzoyl derivative of formula V
and an amount of about 2 to about 10, preferably about 4 to about 7, and most preferably about 5 to about 6 volumes of pyridine per gram of the compound of formula III, and recovering Imatinib base; wherein X is a leaving group selected from the group consisting of: Cl, Br, preferably, Cl; wherein R is either H or an alkyl group, preferably, H; n=0, 1, or 2, preferably n=0 or 2; and HB is an acid, preferably HB is HCl, HI or HBr, more preferably, HB is HCl. Recovering imatinib base provides the crystalline imatinib base of the present invention. The alkyl group is preferably a C1-C6 alkyl group.
The crystalline Imatinib base of the present invention can also be prepared by a process comprising crystallizing imatinib base from a mixture containing pyridine.
The mixture containing pyridine may include a solvent, an anti-solvent and pyridine. The crystallization is performed by a process comprising providing a solution containing imatinib base or salt thereof, pyridine and the said solvent, and adding an anti-solvent to obtain a precipitate of the said crystalline imatinib base; wherein when imatinib salt is used, the mixture comprises also an additional base.
Typically, said solvent includes a solvent that dissolves pyridine, preferably, water, a water-miscible organic solvent or mixtures thereof. Preferably, the water-miscible organic solvent is selected from the group consisting of: dimethylformamide, dimethylacetamide, tetrahydrofuran, alcohol, acetone, acetonitrile, dioxane, dimethylsulfoxide, and mixtures thereof. Preferably, the alcohol is C1-3 alcohol, more preferably, methanol, ethanol, propanol or isopropanol. More preferably, the solvent is dimethylformamide, dimethylacetamide, tetrahydrofuran, or water, most preferably, water.
The additional base can be an organic base or an inorganic base. Preferably, the organic base is a tertiary amine, such as diisoproylethylamine or triethylamine. A tertiary amine is typically of the formula NR3, where each substituent R is independently selected from a C1-C6 alkyl group. Preferably, the inorganic base is sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate or ammonia. More preferably, the base is ammonia.
The solution is provided by heating the combination of imatinib base or salt, the said solvent, pyridine and optionally the additional base. Preferably, the combination is heated to a temperature of about 5° C. to about 70° C., more preferably, to about 40° C. to about 50° C. The Imatinib salt includes but is not limited to Imatinib hydrochloride or Imatinib mesylate. Optionally, when Imatinib salt is used, the process can be performed without heating.
Usually, pyridine is present in the solution in an amount of about 2 to about 10 volumes per gram of Imatinib base or salt. The solution can be also characterized by an amount of pyridine of about 50% to about 70% volume per volume of solution
In the process of the present invention, the addition of the anti-solvent to the solution may provide said mixture. Preferably, the mixture is a slurry. The anti-solvent can be the same as the solvent or a different solvent. Preferably, the anti-solvent is water.
Usually, pyridine is present in the slurry in an amount of about 5% to about 30% volumes per the total volume of solvent and anti-solvent combined, more preferably, of about 10% to about 20% per the total volume of solvent and anti-solvent.
The crystallization process may further comprise cooling the slurry, and maintaining the cooled slurry, to increase the yield of the said crystalline Imatinib base. Preferably, cooling may be carried out to a temperature of about 30° C. to about 0° C., more preferably, to about 20° C. to about 15° C. Preferably, the cooled slurry is maintained for about 1 hour to about 24 hours, more preferably, for about 14 hours to about 16 hours.
The crystallization process may further comprise recovering the precipitated crystalline imatinib base. The recovery may be performed by filtration. The recovered product can be dried. Preferably, the drying is performed at a temperature below 45° C.
The present invention also encompasses amorphous imatinib base. The amorphous Imatinib base can be characterized by the X-ray powder diffraction pattern depicted in
In one embodiment, the amorphous form of the present invention contains less than about 20%, more preferably less than about 10%, and most preferably less than about 5% crystalline form as measured by area percentage XRD.
The amorphous Imatinib base may be prepared by a process comprising lyophilizing a solution of imatinib base in 1,4-dioxane.
Preferably, the solution is provided by combining imatinib base and 1,4-dioxane, and heating the resulting mixture. Preferably, heating is conducted to a temperature of about 50° C. to about 110° C., more preferably to about 90° C. to about 101° C.
Optionally, the solution can be cooled prior to the lyophilization process. Cooling is, preferably, performed to a temperature of about 25° C. to about 12° C.
The lyophilization process may be performed at a temperature of below the freezing temperature of dioxane. Preferably, lyophilization is carried out at a temperature of about 12° C. to about 0° C. Lyophilization is preferably performed at reduced pressures, preferably, at pressures of about 0.01 to about 100 mBar, more preferably about 0.1 to about 15 mBar, most preferably at about 1 mBar.
The present invention encompasses a process for preparing Imatinib salt comprising preparing crystalline or amorphous imatinib base of the present invention, and converting it to imatinib salt. Preferably, the crystalline or amorphous imatinib base is prepared by the processes described herein. Preferably, the Imatinib salt is Imatinib mesylate. The preparation of Imatinib salt from the crystalline or amorphous imatinib base of the present invention may be performed by reacting crystalline Imatinib base with an acid. The reaction can be performed, for example, according to the process disclosed in International Patent Application. No WO1999/03854.
In such method, the amount of acid that may be used is preferably 1 mole equivalent per mole of the starting imatinib base. This is to avoid the formation of the di-acid salt, which occurs when excess of acid is used. (see WO 2005/095379). However, a small excess of acid may be used, such as 0.1 to 0.2 mole equivalent of acid, to ensure completion of transformation of imatinib base to imatinib salt.
When converting the crystalline pyridine solvate discussed above to Imatinib salt, a broader range of the amount of acid, such as 1 mole equivalent to about 1.2 mole equivalent of acid per mole of the starting material crystalline imatinib base, can be used without forming the di-acid salt. The excess of acid, typically, will react with pyridine providing a pyridinium salt, which is soluble in solvents such as alcohols, and remains in the mother liquor while the imatinib salt precipitates.
The above processes preferably prepare a mesylate salt of imatinib. Des-methyl imatinib mesylate of the following formula:
is an impurity of Imatinib mesylate, which is found to be present in the commercial product at levels of at least about 0.09% area by HPLC. The level of the impurity is measured by area percent, preferably, by an HPLC method as described below. Since this impurity is structurally related to Imatinib mesylate, the purification of imatinib mesylate from it is difficult, and purification methods such as crystallization are found to be not efficient for removing it.
In one embodiment, the present invention encompasses Imatinib mesylate of the following formula
having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate of the following formula.
Preferably, Imatinib mesylate has less than 0.07% area by HPLC, more preferably, less than 0.05% area by HPLC of des-methyl imatinib mesylate.
Typically, the measurement of the content of desmethyl-imatinib mesylate is by area percent units, and can be performed by an HPLC method comprising:
a) combining a sample comprising of Imatinib mesylate and desmethyl-imatinib mesylate with water to obtain a solution;
b) injecting the solution to a C18 reversed phase silica based HPLC column;
c) eluting the sample from the column using a gradient eluent of a mixture of 1-butanesulfonic acid sodium salt, KH2PO4 and H3PO4, referred to as mobile phase A, and a mixture of acetonitrile, methanol and tetrahydrofuran, referred to as mobile phase B, and
d) measuring the content of desmethyl Imatinib mesylate using a UV detector.
Desmethyl Imatinib mesylate is a salt of Desmethyl Imatinib. Typically, when transforming Imatinib to imatinib mesylate, by reacting Imatinib with methane sulfonic acid, Desmethyl Imatinib transforms to Desmethyl Imatinib mesylate. In addition, the level of the desmethyl impurity remains similar during this transformation as exemplified in examples 18 and 19.
Accordingly, in order to obtain Imatinib mesylate having less than about 0.09% area by HPLC of desmethyl Imatinib mesylate, imatinib having less than about 0.09% area by HPLC of desmethyl Imatinib should be used as the starting material.
In another embodiment, the present invention encompasses Imatinib of the following formula
having less than about 0.09% area by HPLC of desmethyl-imatinib of the following formula.
Preferably, Imatinib has less than about 0.07% area by HPLC, more preferably, less than about 0.05% area by HPLC of des-methyl imatinib.
Typically, the measurement of the content of desmethyl-imatinib is by area percent units and can be performed by the HPLC method as described above.
The Imatinib having less than about 0.09% area by HPLC of desmethyl-imatinib my be prepared by a process comprising:
The measurement of the content of the desmethyl impurity of formula II may be by area percent units and can carried out by an HPLC method comprising:
The compound of formula I having less than about 0.15% area by HPLC of the desmethyl impurity of formula II is provided by a process comprising crystallizing the compound of formula I from a mixture of water and a C1-3 alcohol.
The crystallization comprises providing a solution of the compound of formula
in a mixture of water and C1-3 alcohol, and precipitating the compound of formula I.
The solution is provided by combining the compound of formula I with a mixture of water and C1-3 alcohol and heating the combination. Preferably, heating is to a temperature of about 55° C. to about 80° C., more preferably, about 65 to about 75° C., most preferably about 75° C.
Preferably, the C1-3 alcohol is isopropanol (“IPA”). Preferably, the ratio of C1-3 alcohol to water in the mixture is of about 80:20, more preferably, of about 60:50, most preferably, 57:43 v/v, respectively. The starting compound of formula I can be prepared, for example, by the process disclosed in Co-pending U.S. Provisional application No. 11/978,227, filed Oct. 26, 2007, as described above, such as by reacting a 4-benzoic acid derivative of the following formula, where X is a leaving group:
with N-methylpiperazine of the following formula;
and reacting the product with HCl to obtain the HCl salt.
Typically, the solution is cooled to induce precipitation of the compound of formula I. Preferably, the solution is cooled to a temperature of about 50° C. to about −5° C., more preferably, to about 35° C. to about 0° C., most preferably, to about 25° C. to about 0° C. The cooling can be performed at once or can be performed step-wise. When performed step-wise, the first cooling is to a temperature of about 35° C. to about 15° C., more preferably, to about 25° C. to about 20° C., and the second is to a temperature of about 5° C. to about −5° C., more preferably, to about 3° C. to about 0° C. Preferably, the first cooling stage is performed over a period of about 0.5 an hour to about 3 hours, more preferably, for about 1 hour to about 1.5 hours. Preferably, the second cooling is performed over a period of about 0.5 an hour to about 5 hours, more preferably, of about 0.5 an hour to about 3 hours, most preferably, of about 1 to about 1.5 hours.
Usually, cooling provides a suspension, which is further maintained at a temperature of about −5° C. to about 5° C., preferably at about 3° C. to about 0° C., to increase the yield of the compound of formula I. Preferably, the suspension is maintained for about 1 hour to about 5 hours, more preferably, for about 1 hour to about 3 hours, most preferably, for about 1 to about 2 hours. Preferably, the cooling and maintaining steps are performed while stirring.
The precipitated compound of formula I is then recovered by any method known to a skilled artisan, such as filtering and drying.
The provided compound of formula I having less than about 0.15% area by HPLC of the desmethyl impurity of formula II is then reacted with the amine of formula III,
to obtain Imatinib having less than about 0.09% area by HPLC of desmethyl imatinib.
The reaction between the compound of formula I and the amine of formula III can be performed, for example, by the process disclosed in U.S. Provisional application No. 11/978,227, filed Oct. 26, 2007.
The process comprises reacting the amine of formula III,
with a 4-[(4-methyl-1-piperazinyl)methyl]benzoyl derivative of formula V
recovering the obtained Imatinib;
wherein n is 0, 1, or 2; X is a leaving group selected from the group consisting of: Cl, and Br, preferably X is Cl; R is either H or a C1-6 alkyl, preferably, H, and HB is an acid selected from the group consisting of: HCl, HBr, HI, Methanesulfonic acid, and para-toluenesulofinic acid, preferably HB is HCl. The process further includes activating the compound of formula I to obtain the activated acid derivative compound of formula V by reacting the compound of formula I,
with a carboxylic acid activating agent in the presence of a base or a water absorbing agent to obtain a reaction mixture comprising the compound of formula V. The mixture comprising the compound of formula V is then used in the above process for preparing imatinib.
Alternatively, imatinib having less than about 0.09% area by HPLC of desmethyl-imatinib can be prepared by crystallizing imatinib, or by combining both methods, i.e., providing the compound of formula I having less than about 0.15% area by HPLC of the compound of formula II, and reacting it with the amine of formula III, followed by crystallizing the obtained imatinib. Preferably, the crystallization is carried out by the process as described above.
The obtained imatinib can then be converted to imatinib mesylate having less than about 0.09% area by HPLC of des-methyl imatinib mesylate. The process comprises measuring the level of the desmethyl-imatinib in at least one batch of imatinib, selecting a batch of imatinib having less than about 0.09% area by HPLC of desmethyl-imatinib; and preparing imatinib mesylate with the selected batch of imatinib.
Des-methyl Imatinib can be converted to another impurity, des-methyl compound of formula IV, during the formation of Imatinib base. The des-methyl impurity of formula IV is found to be difficult to purify from imatinib as exemplified in example 12.
In one embodiment, the present invention encompasses the des-methyl compound of formula IV
Preferably, the present invention encompasses the isolated des-methyl compound of formula IV (3-{4-[4-(4-Methyl-piperazin-1-ylmethyl)-benzoyl]-piperazin-1-ylmethyl}-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide). As used herein, the term “isolated” when referring to des-methyl compound of formula IV means des-methyl compound of formula IV having not more than about 0.15% of des-methyl imatinib. Typically, the measurement of the content of des-methyl imatinib in the des-methyl compound of formula IV is by area %, preferably, by HPLC.
The des-methyl impurity of formula IV can be characterized by at least one of data set selected from the group consisting of: 1H NMR (DMSO-d6) spectrum having peaks at about 2.141, 2.329, 2.305, 2.399, 3.463, 3.583, 7.322, 7.325, 7.923, and 10.159 ppm 1H NMR spectrum as depicted in
The above des-methyl compound of formula IV may be prepared by a process comprising reacting des-methyl imatinib of the following formula
and the compound of formula V,
wherein X is a leaving group, HB is an acid, and n is 0, 1 or 2.
Preferably, X is Cl, Br or I; more preferably, X is Cl.
Preferably, HB is HCl, HI or HBr; more preferably, HB is HCl.
Preferably, n is 0 or 2.
Typically, the reaction between des-methyl imatinib and the compound of formula V forms an acid (“HX”) by-product, thus the reaction is performed in the presence of a base that neutralizes this acid. The base can be an organic or inorganic base. Preferably, the organic base is an amine, more preferably, an aliphatic amine or aromatic amine. The aliphatic and the aromatic amines are preferably C1-C8 alkyl or aryl amines. Preferably, the aliphatic amine is selected from the group consisting of: triethylamine (“TEA”), di-isopropylamine (“DIPEA”), N-methylmorpholine, and mixtures thereof. Preferably, the aromatic amine is pyridine. Preferably, the inorganic base is an alkali metal base, more preferably, K2CO3, Na2CO3, NaHCO3, KHCO3 and mixtures thereof. Most preferably, the base is pyridine.
Preferably, the base is present in an amount of at least one mole equivalent per mole of the compound of formula V, depending on the nature of compound V. Preferably, when n is o, at least about 1 mole equivalent of base is sufficient. Preferably, if n is 1, at least about 2 mole equivalent of base should be used, and if n is 2, at least about 3 mole equivalent of base should be used.
Typically, the reaction is performed in the presence of a solvent. Preferably, the solvent and des-methyl imatinib are combined to obtain a mixture. The solvent can be an organic solvent or the base itself (neat reagent). Preferably, the organic solvent is selected from the group consisting of: tetrahydrofuran (“THF”), methyltetrahydrofuran (“MeTHF”), dioxolane, dichloromethane (“DCM”), dimethylformamide (“DMF”), dimethylacetamide (“DMA”), dimethylsulfoxide (“DMSO”), toluene, and mixtures thereof. When an organic solvent is used the solution also comprises an additional base.
Preferably, the solution is then combined with the compound of formula V, providing a reaction mixture. Preferably, the compound of formula V is added to the solution. Preferably, the addition is performed at a temperature of about −10° C. to about −25° C., more preferably, at about 0° C. to about 5° C., most preferably at about 3° C.
Preferably, the reaction mixture is allowed to warm to about 15° C. to about 25° C. followed by adding an additional amount of solvent, if required to make the less viscous.
The reaction mixture may be kept at such temperature for a sufficient time to allow the formation of the des-methyl compound of formula IV, preferably about 3 hours to about 10 hours, more preferably about 4 hours to about 6 hours. Preferably, the second mixture, wherein an additional amount of solvent has been added, is kept at this temperature for about 3 hours to about 10 hours preferably about 6 hours.
The obtained des-methyl compound of formula IV may be recovered by any conventional methods known in the art, such as extractions and drying.
The des-methyl compound of formula IV can then be used to test the purity of imatinib. In one embodiment, the present invention encompasses a process of determining the presence of the des-methyl compound of formula IV in Imatinib by a process comprising carrying out HPLC or TLC with the des-methyl compound of formula IV as a reference standard.
Preferably, the method comprises (a) measuring by HPLC or TLC the relative retention time (referred to as RRT, or RRF, respectively) corresponding to the des-methyl compound of formula IV in a reference standard sample; (b) determining by HPLC or TLC the relative retention time corresponding to the des-methyl compound of formula IV in a sample comprising the des-methyl compound of formula IV and imatinib; and (c) determining the relative retention time of the des-methyl compound of formula IV in the sample by comparing the relative retention time (RRT or RRF) of step (a) to the RRT or RRF of step (b).
In another embodiment, the present invention encompasses a process of determining the amount of the des-methyl compound of formula IV in a sample comprising the des-methyl compound of formula IV and imatinib by a process comprising carrying out HPLC with the des-methyl compound of formula IV as a reference standard.
Preferably, the above process comprises: (a) measuring by HPLC the area under a peak corresponding to the des-methyl compound of formula IV in a reference standard comprising a known amount of the des-methyl compound of formula IV; (b) measuring by HPLC the area under a peak corresponding to des-methyl compound of formula IV in a sample comprising des-methyl compound of formula IV and imatinib; and (c) determining the amount of the des-methyl compound of formula IV in the sample by comparing the area of step (a) to the area of step (b).
The HPLC method used to make the above analysis is, preferably, the same method used to measure the content of des-methyl imatinib and des-methyl imatinib mesylate.
Imatinib can be purified from the des-methyl compound of formula IV when converted to imatinib mesylate. The purification can be performed, for example according to the process disclosed in commonly assigned U.S. application Ser. No. 11/796,573, incorporated herein by reference.
The process comprises providing a solution of imatinib mesylate and a mixture of water and ethanol; and precipitating by maintaining the solution at a temperature of about 0° C. to about −30° C. to obtain a suspension containing imatinib mesylate.
The obtained imatinib mesylate has a sufficient low amount of the des-methyl compound of formula IV, preferably, less than about 0.15% area by HPLC of the des-methyl impurity IV, more preferably less than about 0.10% area by HPLC of the des-methyl impurity IV. Typically, the measurement of the content of the des-methyl impurity of formula IV in imatinib mesylate is by area % units, preferably by HPLC.
The obtained Imatinib mesylate can be used for preparing pharmaceutical compositions.
In one embodiment, the present invention encompasses a pharmaceutical composition comprising imatinib mesylate having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate and at least one pharmaceutically acceptable excipient.
In another embodiment, the present invention encompasses a process for preparing the pharmaceutical composition, comprising combining imatinib mesylate having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate and the pharmaceutically acceptable excipient.
In yet another embodiment, the present invention encompasses the use of imatinib mesylate having less than about 0.09% area by HPLC of desmethyl-imatinib mesylate in the manufacture of a pharmaceutical composition for the treatment of various types of cancer, atherosclerosis, thrombosis, restenosis, or fibrosis.
“Therapeutically effective amount” means the amount of the purified imatinib mesylate, when administered to a patient for treating a disease or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease or condition. The “therapeutically effective amount” will vary depending on the purity, the disease or condition and its severity, and the age, weight, etc. of the patient to be treated. Determining the therapeutically effective amount of a given pure imatinib mesylate is within the ordinary skill of the art, and requires no more than routine experimentation.
Pharmaceutical formulations of the present invention contain the purified imatinib mesylate produced by the processes of the present invention. In addition to the active ingredient(s), the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
Diluents may be added to the formulations of a present invention. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage for containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL®, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate, dehydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
Solid pharmaceutical compositions that are compacted into dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatine, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL®), hydroxypropyl methyl cellulose (e.g., METHOCEL®), liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON® PALSDONE®), pregelatinized starch, sodium alginate, and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL®, PRIMELOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB®), and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition, and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
When a dosage form such as tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion, and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
Flavouring agents and flavour enhancers make the dosage form more palatable to the patient. Common flavouring agents and flavour enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance, and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions prepared using purified Imatinib mesylate produced by the processes of the present invention, Imatinib mesylate and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
Liquid pharmaceutical compositions may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatine guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xantham gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated, hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
A liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic, administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
The dosages may be conveniently presented in unit dosage form, and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
The oral dosage form of the present invention is preferably in the form of an oral capsule having a dosage of about 10 mg to about 160 mg, more preferably from about 20 mg to about 80 mg, and most preferably capsules of 20, 40, 60, and 80 mg. Daily dosage may include 1, 2, or more capsules per day.
The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin, and, optionally, contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colorant.
A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended, and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet, and then compacted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules.
Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is know to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
The active ingredient and excipients may be formulated into compositions and dosage forms according to methods know in the art.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Analytical method for determination of the desmethyl impurity of formula II in the compound of formula I.
Typical retention times are:
The detection limit is 0.01%.
Typical retention times are:
The detection limit is 0.01%.
PXRD diffraction was performed on X-Ray powder diffractometer: Philips X'pert Pro powder diffractometer, CuKα radiation, λ=1.5418 Å. Single-point detector; scan rate 3°/min. and multi-channel X'Celerator detector active length (2 theta)=2.122°; scan rate 6°/min laboratory temperature 22-25° C.
DSC measurements were performed on Differential Scanning Calorimeter DSC823e (Mettler Toledo). Al crucibles 40 μl with PIN were used for sample preparation. Usual weight of sample was 1-5 mg. Nitrogen as purging gas; 50 ml/min.
Program 1: temperature range 50° C.-100° C., 10° C./min than 100° C.-250° C., 40° C./min.
Program 2: temperature range 50° C.-250° C., 10° C./min.
To a solution of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyridineamine (80 g) in pyridine (400 g) was added 4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride dihydrochloride (1.1 eq) at 0° C. The reaction was kept under stirring at 15-20° C. for 1 h, and then water (400 mL) was added. The mixture was heated up to 40° C., then 26% NH4OH (200 g) and water (900 g) were added. The reaction mixture was kept under stirring at room temperature overnight. The solid was filtered off, washed with water and dried at 45° C. under vacuum for 3-4 h. Imatinib was obtained as a yellowish powder (135 g, 95% yield, >98% purity).
To a suspension of 4-[(4-methyl-1-piperazinyl)methyl]benzoic acid (84 g) in pyridine (400 g) was added SOCl2 (44.8 g, 1.05 eq) is added and the mixture is kept under stirring at 30-50° C. for 1-2 h at 0° C. After cooling to 0° C., N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyridineamine (80 g) was added. The reaction was kept under stirring at 15-20° C. for 1 h, and then water (400 mL) was added. The mixture was heated up to 40° C., then 26% NH4OH (200 g) and water (900 mL) were added. The reaction mixture was kept under stirring at room temperature overnight. The solid was filtered off, washed with water and dried at 45° C. under vacuum overnight. Crystalline Imatinib base of the present invention was obtained as a yellowish powder (125 g, 88% yield, >98% purity).
To a suspension of 4-[(4-methyl-1-piperazinyl)methyl]benzoic acid dihydrochloride (30 g) in pyridine (100 g) was added SOCl2 (11.5 g, 1.05 eq) at 20° C., and the mixture was kept under stirring at 45-50° C. for 1-2 h. After cooling to 0° C., N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyridineamine (20 g) were added. The reaction was kept under stirring at 15-25° C. for 1 h, and then water (100 mL) was added. The mixture was heated up to 40° C., then 26% NH4OH (50 g) and water (225 mL) were added. The reaction mixture was kept under stirring at room temperature for overnight. The solid was filtered off, washed with water and dried at 45° C. under vacuum for overnight. Crystalline Imatinib base of the present invention was obtained as a yellowish powder (32 g, 90% yield, >98% purity).
28% NH3 (30 mL) was added at 40° C. to a solution of imatinib mesylate (60 g) in a mixture of pyridine (140 mL) and water (70 mL). The solution was kept under stirring at 40° C. until precipitation of imatinib base occurred. Additional amount of water (490 mL) was added at 40° C., then the mixture was allowed to spontaneously reach room temperature and it was kept under stirring for 15 h. The solid was filtered off, washed with water and dried under vacuum at 40° C. overnight. Crystalline Imatinib base of the present invention was obtained as a yellowish solid (50 g, 90% yield).
To a solution of Imatinib base (94 g) in pyridine (376 g) and water (188 g) at 40-50° C., water (1300 g) was added. The mixture was kept under stirring at 15-20° C. overnight, then the solid was filtered off, washed with water and dried at 40° C. under vacuum for 16 h. Imatinib base was obtained as a yellowish solid (99.6 g, >99% purity).
37% HCl (9 mL) was added to a suspension of imatinib base (50 g) in a mixture of pyridine (140 mL) and water (70 mL). The solution was heated up to 40° C., treated with charcoal and filtered. 28% NH3 (30 mL) was added to the filtrate (pH=9.3) at 40° C. and the solution was kept under stirring at 40° C. until precipitation of imatinib base occurred. Additional of water (490 mL) was added at 40° C., then the mixture was allowed to spontaneously reach room temperature and it was kept under stirring for 15 h. The solid was filtered off, washed with water and dried under vacuum at 40° C. overnight. Crystalline Imatinib base of the present invention was obtained as a yellowish solid (50 g, 90% yield).
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]aminophenyl]benzamide (98.6 g) was added to EtOH (1.4 L). To the suspension methanesulfonic acid (19.2 g) was added dropwise. The solution was heated under reflux for 20 min and then filtered clear at 65° C. The filtrate was evaporated down to 50% and the residue filtered off at 25° C. (filtered material A). The mother liquor were evaporated to dryness. This residue and filtered material A were suspended in EtOH (2.2 L) and dissolved under reflux with addition of water (30 mL). The solution was cooled down and kept overnight at 25° C. The solid is filtered off and dried at 65° C.
Imatinib base (500 mg) was dissolved in 1,4-dioxane (10 ml) at 90° C. The solution was allowed to cool to 25° C. and put to the freezer at −30° C. where the solution was frozen. The frozen solution was transferred to the lyophylisator and vacuum 1 mBar was applied, which provided the freeze drying of 1,4-dioxane affording amorphous imatinib base.
A suspension of compound I in a mixture of water (320 mL) and IPA (420 mL) was heated at 75° C. in order to obtain a clear solution. Under vigorous stirring, the reaction mixture was cooled down to 20-25° C. in 1 hours, then to 0-3° C. in 1-1.5 h and kept under stirring at this temperature for 1-2 h. The solid was filtered off and the solid cake was washed with IPA (180 mL). The product was dried at 60-65° C. under vacuum for 15 h. Pure compound (I) was obtained as a white solid (131 g).
A mixture of 4-chloromethylbenzoic acid (10 g, 58.6 mmol) and piperazine (20 g, 232 mmol) in n-BuOH (100 g) was heated at 50° C. for 3 h, then kept at room temperature overnight. The solid was filtered off, washed with n-BuOH and dried at 70° C. overnight. Desmethyl impurity (II) was obtained as a white solid (17.5 g, 86.6% purity).
4-Chloromethylbenzoyl chloride (15 g) was added to a mixture of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyridineamine (18.5 g), K2CO3 (20 g) in THF (370 g) at 2-3° C. The mixture was kept under stirring at 2-7° C. for 1 h, then at 15-20° C. for additional 3 h. Water (700 g) was added and the suspension was kept under stirring at 15-20° C. for 1 h. The solid was filtered off, washed with water and dried at 65° C. under vacuum for 15 h to furnish the title product (27 g, 94% yield).
Cp9665 (14 g) was added portion wise in 15 min to a solution of piperazine (28.4 g) in EtOH (22 g) and water (27.5 g) at 50° C. The reaction mixture was refluxed for 2 h, then cooled down to room temperature and kept under stirring overnight. The solid was filtered off, washed with a mixture of water (13.75 g) and EtOH (11 g) and taken up with water (400 g) and AcOEt (100 g). After addition of 28% NH3 (25 g), the mixture was kept under stirring overnight. The solid was filtered off, washed with water and dried at 70° C. under vacuum for 15 h to furnish the desired product (12 g).
37% HCl (9 mL) was added to a suspension of imatinib base (50 g, desmethyl 0.12%) in a mixture of pyridine (140 mL) and water (70 mL). The solution was heated up to 40° C., treated with charcoal and filtered. 28% NH3 (30 mL) was added to the filtrate (pH=9.3) at 40° C. and the solution was kept under stirring at 40° C. until precipitation of imatinib base occurred. Additional of water (490 mL) was added at 40° C., then the mixture was allowed to spontaneously reach room temperature and it was kept under stirring for 15 h. The solid was filtered off, washed with water and dried under vacuum at 40° C. overnight. Imatinib base was obtained as a yellowish solid (50 g, 90% yield, 0.08% desmethyl content).
This crystallization, however, didn't succeed in decreasing the level of the des-methyl impurity of formula IV. The starting imatinib base had 0.55% of the des-methyl impurity of formula IV, and so did the crystallized imatinib base.
To a suspension of compound I (n=2, X—═Cl) (20 g, containing 0.13% of the des-methyl impurity II) in toluene (35 mL) and DMF (1 mL) under N2 at 60° C., (20 g) was added over a period of 1 h SOCl2. The mixture was kept under stirring at 62° C. for 20 h. After cooling at 20° C., toluene (20 mL) was added and the mixture was stirred for 0.5 h. The solid was filtered off, washed with toluene (50 mL) and dried at 65° C. under vacuum for 15 h. The product was obtained as a white powder (21 g). To a solution of the amine of formula III (R═H) (1.5 kg,) in pyridine (8.25 L) at 0° C., was added as solid in one portion under N2 compound I (n=2; X═Cl) (2.69 kg). The temperature increased spontaneously to 5-10° C. The reaction was kept under stirring at 15-20° C. for 2 h, then water (8.25 L) was added allowing the temperature to increase, then the mixture was heated up to 35-40° C. Charcoal Norit S2 (75 g) was added and the mixture was stirred at 40° C. for 30 min, then filtered over dicalite bed. The panel was washed with water (6 L). 28% NH4OH (4.05 L) was added to the filtrate and the mixture was kept under stirring for 15-30 min, in order to obtain the product precipitation (mixture pH=9.4). Water (15.2 L) was added and the reaction mixture was kept under stirring at 20° C. for 15 h. The solid was filtered off, washed with water and dried at 40° C. under vacuum for 8 h. Imatinib was obtained as a yellowish powder (2.98 kg, 93% yield, desmethyl imatinib 0.08%).
MeSO3H (2.4 g) was added to a solution of desmethyl imatinib (12 g) in MeOH (240 g) at 60° C. The solvent was evaporated under vacuum and the residue was taken up with EtOH (72 g) and AcOEt (360 g). The mixture was stirred at room temperature overnight, then the solid was filtered off, washed with AcOEt and dried under vacuum at 75° C. to furnish the title product (13.9 g).
4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride dihydrochloride (4 g) was added to a solution of desmethyl imatinib (III) (5 g) in pyridine (25 mL) at 3° C. The mixture was allowed to reach room temperature, then additional pyridine (25 mL) was added and the mixture was stirred at room temperature for 6 h. Water (50 mL) and 28% NH3 were added and the mixture was evaporated to dryness under vacuum. The residue was taken up with DCM and water. The organic phase was separated and evaporated to dryness to furnish the title compound as a yellowish powder (4 g).
The coating was peeled off from 5 tablets and the remainder was milled in a mortar. 20 mg of the powder were taken up with 4 mL of mobile phase B and 16 mL of mobile phase A. The mixture was sonicated for 5 min and then filtered. The filtrate was injected in HPLC.
Imatinib mesylate (4.2 g, containing 0.08% of desmethyl imatinib) was added to MeOH (10.5 mL) and the mixture was heated at 60° C. The solution was allowed to cool to 20° C. under stirring. After 30 min stirring at 20° C., the solid was filtered off and dried under vacuum at 100° C. to furnish imatinib mesylate (3.8 g, containing 0.08% of desmethyl imatinib).
Imatinib mesylate (4.2 g, containing 0.39% of desmethyl imatinib) was added to MeOH (10.5 mL) and the mixture was heated at 60° C. The solution was allowed to cool to 20° C. under stirring. After 30 min stirring at 20° C., the solid was filtered off and dried under vacuum at 100° C. to furnish imatinib mesylate (3.8 g, containing 0.38% of desmethyl imatinib).
Imatinib base (60 g; 0.1216 mole) was suspended in 1200 ml of Ethanol and stirred. Reactor was kept under flow of nitrogen during all of the experiment (6 litres per hour). Then, 24 ml of water was added to the suspension and the temperature was adjusted at −15° C. An ethanolic solution of methanesulfonic acid (79.8 ml 10% V/V; 0.1213 mole) was added during 2 minutes to the reaction mixture. Temperature of the solution was set at −10° C. during 10 minutes, imatinib base was dissolved and seeding material of form X (2 g) was added. The crystallization process was continued under stirring for 190 minutes and temperature was continuously increased to −5° C. The suspension was stored overnight in a freezer at approx. −27° C. Then, suspension was diluted by 1000 ml TBME, filtered by nitrogen pressure and obtained crystalline portion was washed with 400 ml TBME. The resulted crystalline form was dried by flow of nitrogen through the filter to remove free ethanol. Ethanol content was about 7.5%. (Yield was 67.95 g; 85%)
The present application claims the benefit of the following U.S. Provisional Patent Application Nos. 60/854,774, filed Oct. 26, 2006; 60/874,420, filed Dec. 11, 2006; 60/958,367, filed Jul. 5, 2007; 60/963,238, filed Aug. 2, 2007; 60/967,617, filed Sep. 5, 2007; 60/995,332, filed Sep. 25, 2007; 60/860,624, filed Nov. 22, 2006; 60/979,256, filed Oct. 11, 2007; 60/934,911, filed Jun. 14, 2007; and 60/997,849, filed Oct. 5, 2007. The contents of these applications are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60854774 | Oct 2006 | US | |
| 60874420 | Dec 2006 | US | |
| 60958367 | Jul 2007 | US | |
| 60963238 | Aug 2007 | US | |
| 60967617 | Sep 2007 | US | |
| 60995332 | Sep 2007 | US | |
| 60860624 | Nov 2006 | US | |
| 60979256 | Oct 2007 | US | |
| 60934911 | Jun 2007 | US | |
| 60997849 | Oct 2007 | US |
