MXPA06008491A - Crystal forms of e-2-methoxy -n-(3-{4-[3-methyl -4-(6-methyl- pyridin-3 -yloxy)-phenylamino]-quinazolin-6-yl} -allyl)- acetamide - Google Patents

Abstract

Crystal forms of E-2-Methoxy-N-(3- {4-[3-methyl- 4-(6-methyl-pyridin -3-yloxy)- phenylamino]-quinazolin -6-yl}-allyl) -acetamide. A crystal form is useful in the synthesis of salts and complexes of E-2-Methoxy-N-(3-{4- [3-methyl-4-(6 -methyl-pyridin-3-yloxy) -phenylamino]-quinazolin -6-yl}-allyl) -acetamide. A crystal form also improves stability of tabletted or capsuled E-2-Methoxy-N-(3- {4-[3-methyl- 4-(6-methyl-pyridin -3-yloxy) -phenylamino]-quinazolin -6-yl}-allyl)-acetamide as a drug product.

Description

CRYSTALLINE FORMS OF E-2-METOXY-N- (3- { 4- [3-METHYL-4- (6-METlL-PYRIDIN-3- ILOXY) -FENILAMINO] -QUINAZOLIN-6-IL. ALIL) -ACETAMIDE FIELD OF THE INVENTION This invention relates to crystalline forms of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] - quinazolin-6-yl.}. -alyl) -acetamide with the formula I: BACKGROUND OF THE INVENTION Formula I in its free base form is described in International Publication, International Patent No. WO 01/98277 published December 27, 2001, the disclosure of which is hereby incorporated by reference herein by reference. its entirety The above request is assigned in common with the present application. The free base of formula I is useful in the treatment of hyperproliferative diseases, such as malignant tumors.

The succinate and malonate forms, including the sesquisuccinate and dimallonate forms of E-2-methoxy-N- (3. {4- [3-meth] I-4- (6-methyl-pyridin-3-yloxy) ) -phenylamino] -quinazolin-6-yl.}. -alyl) -acetamide were described in the US provisional patent application. Serial No. 60/340885, filed December 12, 2001, incorporated herein by reference.

The complexes and salts of E-2-methoxy-N- (3. {4- [3-methyl-4- (6-methyl-plridin-3-yloxy) -phenylamino] -quinazolin-6-yl} .alpha.) -acetamide which can be prepared from a crystalline form of free base can be the active agent of pharmaceutical compositions, as described in the U.S. patent application Ser. Serial No. 10 / 738,972, filed December 17, 2003, incorporated herein by reference. These complexes and salts are useful in the treatment of hyperproliferative diseases, such as malignant tumors, in mammals, especially humans. The aforementioned forms of formula I represent a significant advance in the art insofar as these forms of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl- pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl.} - allyl) -acetamide are useful in the treatment of hyperproliferative diseases. Thus it is important that the compound is responsible for the synthesis of the important salts and complexes of that compound. In addition, it is required that the product, used as a drug, be stable when it is produced in pharmaceutical forms.

SUMMARY OF THE INVENTION It has now been discovered that the crystalline forms of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino]] -quinazolin-6-yl.} - allyl) -acetamide are useful in the synthesis of salts and complexes of the title compound. The use of these stable crystalline forms improves the purity of the title compound. These stable forms also attenuate stability problems associated with tablet or capsule forms of the compound as a medicament. In accordance with the present invention, crystalline forms of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] are described] -quinazolin-6-yl.}. -alyl) -acetamide with the following formula I: The crystalline form of the compound of the present invention includes Form A and hydrates and / or solvates thereof; Form B and hydrates and / or solvates thereof; Form C and hydrates and / or solvates thereof; Form F and hydrates and / or solvates thereof; Form G and hydrates and / or solvates thereof and Form H and hydrates and / or solvates thereof.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention can be better understood by reference to the drawings of which: Figure 1 is a diffractogram of Crystalline Form A of E-2-Methoxy-N- (3-. {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl] -allyl) -acetamide; Figure 2 is a diffractogram of the crystalline form B of E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) ) -phenylamino] -quinazolin-6-yl.}. -alyl) -acetamide; Figure 3 is a diffractogram of crystalline form C of E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylam No] -quinazolin-6-yl.}. -alyl) -acetamide; Figure 4 is a diffractogram of the crystalline Form F of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy)) phenylamino] -quinazolin-6-yl.} - allyl) -acetamide; Figure 5 is a diffractogram of crystalline Form G of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] - quinazolin-6-yl.} - allyl) -acetamide; Figure 6 is a diffractogram of the crystalline form H of E-2-Methoxy-N- (3- {4- 4- methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamide. no] -quinazolin-6-yl.}. -alyl) -acetamide; and Figure 7 is a solid-state NMR spectrum of Crystalline Form A of E-2-Methoxy-N- (3. {4- [3-methyl-4- (6-methyl-pyridine- 3-yloxy) -phenylamino] -quinazolin-6-yl.} - allyl) -acetamide.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to crystalline forms of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylam) No] -quinazolin-6-yl.}. -ali) -acetamide with the formula I: formula I Although the present invention is directed to crystalline forms of E-2-methoxy-N- (3- {4- [S-methyl} -ie-methyl-pyridin-S-yloxy] -phenylamino-quinazolin-e-ilJ -alylJ-acetamide, in a preferred embodiment, six crystalline forms are provided, Those skilled in the art are aware that other forms can be synthesized by modifications to the synthesis methods employed in the preparation of the crystalline forms described herein. These shapes are characterized by their X-ray powder diffraction models, which have been identified in a Bruker D5000 diffractometer using copper radiation (wavelength 1: 1.54056) .The voltage and current intensity of the tube were adjusted to 40 kV and 50 mA, respectively, the divergence and dispersion slits were adjusted to 1 mm and the reception slit was adjusted to 0.6 mm, diffracted radiation was detected by a Kevex PSI detector. continuous theta-2theta at 2.4 min (et apa of 1 sec / 0.04 °) from 3.0 to 40 ° 29. An alumina pattern was analyzed to check the alignment of the instrument. Data was collected and analyzed using Bruker axis Version 7.0 software. Samples were prepared by placing them on a quartz support. It should be noted that Bruker Instruments acquired Siemans; thus, the Bruker D5000 Instrument is essentially the same as a Siemans D5000. General synthetic methods that can be referred to prepare substituted bicyclic derivations of which the crystalline forms of the present invention are related are provided in the international patent WO 01/98277 (published on December 27, 2001), the EE patent .US. 5,747,498 (issued May 5, 1998), U.S. patent application Ser. serial number 08/953078 (filed October 17, 1997), international patent WO 98/02434 (published January 22, 1998), international patent WO 98/02438 (published January 22, 1998), WO 96/40142 (published December 19, 1996), WO 96/09294 (published March 6, 1996), WO 97/03069 (published January 30, 1997). , the international patent WO 95/19774 (published on July 27, 1995) and the international patent WO 97/13771 (published on April 17, 1997). Additional procedures are referred to in U.S. patent applications. numbers 09 / 488,350 (filed on January 20, 2000) and 09 / 488,378 (filed on January 20, 2000). The above patents and patent applications are incorporated herein by reference in their entirety. Certain starting materials can be prepared according to methods known to those skilled in the art and certain synthetic modifications can be made according to methods known to those skilled in the art. A classical procedure for preparing 6-iodoquinazolinone is provided in Stevenson, T.M., Kazmierczak, F., Leonard, N.J., J. Org. Chem. 1986, 51, 5, p. 616. Couplings of boronic acid catalysed with palladium are described in Miyaura, N., Yanagi, T., Suzuki, A. Syn. Comm. 1981, 11, 7, p. 513. Heck couplings catalysed with palladium are described in Heck et. to the. Organic Reactions, 1982, 27, 345 or Cabri et. to the. in Acc. Chem. Res. 1995, 28, 2. For examples of the palladium-catalyzed coupling of terminal alkynes to aryl halides see: Castro et. to the. J. Org. Chem. 1,963, 28, 3,136 or Sonogashira et. to the. Synthesis, 1977, 777. Terminal alkyne synthesis can be carried out using appropriately substituted / protected aldehydes as described in: Colvin, E. W. J. et. to the. Chem. Soc. Perkin Trans. I, 1977, 869; Gilbert, J. C. et. to the. J. Org. Chem., 47, 10, 1982; Hauske, J. R. et. to the. Tet. Lett. , 33, 26, 1992, 3715; Ohira, S. et. to the. J. Chem. Soc. Chem. Commun., 9, 1992, 721; Trost, B. M. J. Amer. Chem. Soc, 119, 4, 1997, 698 or Marshall, J. A. et. to the. J. Org. Chem., 62, 13, 1997, 4.313. A first crystalline form of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl) .}. -alil) -acetamide is Form A. Form A is characterized by its intensities and positions of maximum value of the diffraction lines, as explained in Tables 1 to 3. These tables list values 2- Theta for the anhydride of Form A. However, hydrates and solvates are also within the scope of the present invention. The intensities and the positions of the most pronounced maximum values of the diffraction lines are explained in Table 1. It is observed that the experimental error in positions as in all the Tables in the present specification is +/- 0.2 Theta.

TABLE 1 The intensities and the positions of the most pronounced maximum values of the diffraction lines of Form A are explained in Table 2. TABLE 2 The intensities and positions of the maximum values of the pronounced diffraction lines of Form A are explained in Table 3. TABLE 3 In addition, Form A is characterized by single-crystal X-ray analysis. The data from the single-crystal X-ray analysis is obtained at room temperature using a Bruker X-ray diffractometer equipped with copper radiation and graphite monochromators. The structures were solved using direct methods. The SHELXTL computer library provided by Bruker AXS, Inc. facilitated all necessary crystallographic calculations and molecular visualizations. The monocrystal X-ray analysis of Form A is as follows: Form A Empirical formula C2 H2 NdO3 Formula weight 469.54 Glass size (mm) 0.24 x 0.08 x 0.06 Monoclinical space group P21 (1) / n Unit cell dimensions a = 9.456 Á b = 9.237 Á c = 27,947 Á a = 90 ° β = 92,97 ° y = 90 ° Z (by formula) 4 Density (g / cm 3) 1,279 R 0,0664 To compare the results between a single crystal and a powder sample, a powder model calculated from single crystal results can be obtained. The XFOG and XPOW software provided as part of the SHELXTL computer library can carry out this calculation. The SHELXTL computer library has been developed and improved over a long period of time. The most recent version of this work in development is as follows: SHELXTL ™ Reference Manual, Version 5.1, Bruker AXS, Madíson, Wisconsín, EE.UU. (1997). The comparison of the powder model calculated with the experimental powder model confirms whether a powder sample corresponds to a ceded monocrystal structure. The results are indicated in the X-ray powder diffraction models superimposed. The lower model corresponds to the calculated powder model (from monocrystal results) and the upper model corresponds to a representative experimental dust model. A correspondence between the two models indicated the agreement between the dust sample and the corresponding monocrystal structure. Nuclear magnetic resonance data of the solid state (rmn is) for Form A are characterized by a spectrum with the characteristics indicated in Table 4. TABLE 4 Experimental error +/- 0.1 ppm The above spectra were obtained by a procedure in which approximately 80 mg of sample were highly packaged in a 4 mm ZrO rotor for each sample analyzed. All spectra were collected at 295K and atmospheric pressure on a Bruker-Biospin 4 mm CPMAS BL probe placed on a 500 MHz NMR spectrometer, Advance DSX, of Bruker-Biospin of large internal diameter. The samples were placed in the magic angle and rotated at 15.0 kHz, corresponding to the maximum rotation speed specified for the 4 mm rotors. The rapid rotation speed minimized the intensities of the lateral rotation bands. Solid-state spectra of C-13 were collected using a rotation-to-magic-cross-polarization with proton-decoupled magic (CPMAS) experiment. The proton decoupling field of approximately 85 kHz was applied. The number of sweeps (600) was adjusted to obtain adequate signal-noise (S / N). The recirculation delay was adjusted to 6 seconds. The spectra were referenced using an external crystalline adamantane standard, adjusting their resonance to high field at 29.5 ppm. The maximum values of low intensity in the spectrum to 34.3; 30.3; 28.3 as well as all maximum values at chemical shifts less than 15 ppm are lateral rotation bands. A second crystalline form of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -alil) -acetamide is Form B. The 2-theta values and the intensities of Form B, as a hydrate or a solvate, are explained in Table 5. The present invention also considers the anhydrous form. TABLE 5 A third crystalline form of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-) il.}. -alil) -acetamide is Form O As in Forms A and B, Form C is identified by the intensities and positions of the maximum values of the diffraction lines for that form, its hydrates and / or its solvates. The 2-theta values and intensities of a hydrate of Form C are explained in Tables 6 to 8. However, Form C anhydrous and the solvates thereof are also within the consideration of the present invention. Tables 6 to 8 present 2-theta values and intensities the most pronounced, most pronounced and pronounced, respectively, of Form C.

TABLE 6 TABLE 7 20 TABLE 8 fifteen twenty A fourth crystalline form of E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-p. l.}. -alyl) -acetamide is Form F. Form F is also identified by the intensities and positions of the maximum values of the diffraction lines for a hydrated form, in Tables 9 to 11. However, the Form F anhydrous and the solvates are within the consideration of the present invention. Tables 9 to 11 present 2-theta values and intensities, the most pronounced, most pronounced and pronounced, respectively, of Form F. TABLE 9 TABLE 10 TABLE 11 fifteen twenty A fifth crystalline form of E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} .alpha.) -acetamide is Form G. Form G, like the forms discussed above, is characterized in Tables 12 to 14. Specifically, a hydrate of Form G is provided therein. However, anhydrous Form G and the solvates of Form G are within the scope of the present invention.

Tables 12 to 14 show 2-theta values and intensities, the most pronounced, most pronounced and pronounced, respectively, of Form G. TABLE 12 TABLE 14 fifteen twenty A sixth crystalline form of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6) -yl.}. -alyl) -acetamide is Form H. The crystalline Form H of the free base of E-2-Methoxy-N- (3-. {4- [3-methyl-4- (6 -met.lp¡r¡din-3-ioxy) -phenylamino] -quinazolin-6-yl.} - allyl) -acetamide is characterized by the intensities and positions of the maximum values of the diffraction lines summarized in Tables 15 to 17. Specifically, Form H anhydrous, its hydrate or solvate is explained in Tables 15 to 17. The anhydrous form, hydrates and solvates of Form H are within the consideration of the present invention. Tables 15 to 17 present 2-theta values and intensities, the most pronounced, most pronounced and pronounced, respectively, of Form H.

TABLE 15 fifteen TABLE 17 Solvate is defined as a crystalline form of the title compound which includes a ion or solute molecule with one or more solvent molecules. Hydrate is defined as a compound formed by water with the title compound.

Composition is defined as a crystalline form of the title compound with one or more other constituents. Free base is defined as a basic form of an organic amine capable of forming acid salts such as hydrochlorides. The free base formed of Formula I is broadly described in the international publication, international patent No. WO 01498277, incorporated herein by reference in its entirety. The pharmaceutical composition is defined as a crystalline form of the title compound that includes a conventional pharmaceutical carrier or excipient. In addition, the composition may include other medicinal or pharmaceutical agents, vehicles, adjuvants and the like. The pharmaceutical composition may be in a form suitable for oral administration as a tablet, a capsule, a pill, a powder, a prolonged-release formulation, a solution, a suspension, a sterile solution, suspension or emulsion for parenteral injection, an ointment or cream for topical administration or a suppository for rectal administration. The pharmaceutical composition can be in unit dosage forms suitable for single administration of precise dosages. The following examples are provided to illustrate the present invention. Because these examples are given for illustrative purposes only, the invention should not be considered limited thereto. Example 1 Crystalline Form A of E-2-Methoxy-N- (3-f4-f3-methyl-4-f6-methyl-pyridin-3-yloxy) -phenylamino-quinazolin-6-yl} -alyl) -acetamide Synthesis of 6-lodo- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazoline: A 3-neck flask was equipped with a mechanical stirrer and kept under N2. The flask was charged with 6-lodo-4-chloroqulnazoline (10.0 g, 34.43 moles) and dry THF (35 ml). After that, 3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamine (7.38 g, 34.43 mmol) and dry THF (45 ml) were added and the yellow suspension to make it boil at reflux. After 15 minutes most of the reactants were placed in solution and a fine yellow suspension was obtained. After 25 min, the internal temperature of the reaction mixture was 56 ° C and precipitation of the desired product began. Heating was continued for an additional 2 hours and the reaction mixture was allowed to cool to room temperature while remaining in the oil bath. Yellow crystals were collected by filtration, washed with cold THF (0 ° C) (1 x 10 ml) and dried at 50 ° C, p < 2x104 Pa (200 mbar). The title compound was obtained as light yellow crystals (15.75g, 98%). Rf = 0.45 (EtOAc / MeOH = 9/1). 1 H NMR (CDCl 3, 300 MHz): d = 11.40 (a s, 1 H, NH); 9.29 (d, J = Hz, 1 H, H-2); 8.91 (s, 1 H, H-2"), 8.36-8.32 (m, 2H, H-7, H-8), 7.74-7.73 (m, 2H, H- 4", H-5); 7.62 (dd, J, = 8.7 Hz, J2 = 2.6 Hz, 1H, H-5"), 7.49-7.46 (m, 2H, H-6 ', H-5); 7.06 (d, J = 8.7 Hz, 1H, H-2 '), 2.54 (s, 3H, CH3), 2.26 (s, 3H, CH3), 13C NMR (CDCl3 + De-DMSO, 75 MHz): d = 159.51, 153.63, 153.17, 152.82, 152.70, 145.26, 141.37, 138.01, 134.75, 134.65; 131.05, 129.10, 128.74, 126.77, 124.86, 124.43, 120.41, 116.98, 94.89, 23.54, 17.67.The title compound had an tR (min) of 12.13 under the following conditions RP-HPLC: Field of Symmetry RP18, 75 x 4.6 mm, Flow 1.0 ml / min, 205/210/220/245 nm, Temp. 25 ° C; Injection volume 10 μl of a 0.5% solution in ACN / H2O 9/1, Eluent: B: ACN, C: 0.01 mmol NH4OAc in H2O pH = 6.0 and Gradient: 0 min: B = 30%, C = 70% and 20 min: B = 85%, C = 15% Synthesis of propargylamide of 2-methoxy-acetic acid: A solution of methoxyacetyl chloride (12.5 ml, 0.137 mol, 1.2 equiv.) In dry CH2Cl2 (45 ml), maintained under N2 was cooled to -40 ° C. A solution of propargylamine (7.98 ml, 0.125 mol, 1.0 equiv.) In dry CH2Cl2 (40 ml) was added over 45 minutes keeping the temperature lower than -25 ° C. After 15 minutes triethylamine (17.4 ml, 0.125 mol, 1.0 equiv.) Was added over 45 minutes keeping the temperature lower than -25 ° C. The reaction mixture was heated to room temperature. TLC after 3 hours showed complete conversion. The reaction mixture was rapidly cooled with H 2 O (50 ml) and the organic phase was washed with a saturated NaCl solution, filtered through cotton and concentrated at a temperature of 40 ° C and a pressure greater than 6.5 × 10 4 Pa (650 mbar). The crude compound was purified by short path distillation (boiling point of 49 ° C and p of 9 Pa (0.09 mbar) .The title compound was obtained as a colorless liquid (7.84 g, 50%) which crystallized leaving it at rest Rf = 0.36 (heptane / EtOAc = 7/3) 1 H NMR (CDCl 3, 300 MHz): d = 6.72 (ace, 1 H, NH), 4.09 (dd, ^ = 5.5 Hz, J2 = 2.6 Hz, 2H, CHz-NH), 3.92 (s, 2H, CHz-OMe), 3.43 (s, 3H, OCH3), 2.24 (t, J = 2.6 Hz, 1H, CH1 alkyne) 13 C NMR (CDCl3, 75 MHz): d = 169.14 (C = O); 79.11 (C-2 '); 71.63 (C-) 2); 71, 41 (C-3 '); 59.04 (OCH3); 28.26 (C-1'). Gas chromatography was used to determine the tR (min) of 6.42 under the conditions shown in the table below.

The preparation of 2-methyl-2-butene (0.59 ml, 5.60 mmol, 2.8 equiv.) Was added for 1 hour to a cold solution (0-5 ° C) of BH3 * THF complex (sun .1.0 M, 3.0 mL, 3.0 mmol, 1.5 equiv.) Maintained under N2. The reaction mixture was stirred at this temperature for 30 minutes followed by the addition of propargylamide of 2-methoxyacetic acid (255 mg, 2 mmol, 1.0 eq) dissolved in dry THF (1 ml) for 15 minutes. The ice bath was removed and the reaction mixture was heated at room temperature for 20 minutes. The reaction mixture was then heated at 35 ° C for 1 hour. K2CO3 (0.55 g) was added; 4 mmoles; 2.0 equiv.) Dissolved in H2O (1.2 ml) degassed for 30 minutes to the reaction mixture. During the addition of the first half gas evolution was observed which was taken during additional addition. 6-Mld- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazoline (1.41 g, 3 mmol, 1.5 equiv.) Was added in three portions giving a yellow suspension. PPh3 (21 mg, 0.08 mmol, 4 mol%) and Pd (OAc) 2 (4.5 mg, 0.02 mmol, 1 mol%) each were added in one portion and the mixture was heated reaction to boil at reflux (65 ° C-68 ° C). After about 30 minutes a yellow solution was obtained and the reaction was monitored by HPLC assay. After 18 hours the reaction mixture was allowed to cool to room temperature followed by the addition of saturated NaCl solution (10 ml) and EtOAc (10 ml). The organic phase was separated, washed with H2O (5 ml) and concentrated at 50 ° C and a pressure less than 2x104 Pa (200 mbar). Purification by plug filtration, SiO2, EtOAc / MeOH = 9/1. The title compound was obtained as light yellow crystals (0.55g, 59%). Rf = 0.16 (EtOAc / MeOH = 9/1). 1 H NMR (CDCl 3, 250 MHz): d = 8.71 (s, 1 H, H-2); 8.25 (d, J = 1.7 Hz, 1H, H-8); 7.90 (s, 1H, H-7); 7.82 (s, 1H, NH); 7.79 (s, 1H, H-5); 7.66 (d, J = 2.5 Hz, 1H, H-4"), 7.54 (dd, ^ = 8.7 Hz, J2 = 2.6 Hz, 1H, H-5"); 7.15-7.07 (m, 2H, H-5 ', H-6'); 6.91 (d, J = 8.7 Hz, 1H, H-2 '); 6.83 (at t, 1H, NH); 6.65 (d, J = 15.9 Hz, 1H, H-9); 6.34 and 6.29 (dt, J., = 15.9 Hz, J2 = 6.1 Hz, 1H, H-10); 4.14 (dt, J = 6.1 Hz, 2H, CHzOMe); 3.97 (s, 2H, CHzNH); 3.45 (s, 3H, OCH3); 2.53 (s, 3H, CH3); 2.29 (s, 3H, CH3). 13 C NMR (CDCl 3, 75 MHz): d = 169.76 (C = O); 157.90; 154.93; 152,367; 152.23; 150.90; 149.74; 139.34; 134,73; 134.63; 131.16; 130.77; 130.36; 128.85; 129.98; 125.47; 124.66; 123.65; 121.32; 119.51; 119.13; 115.39; 71.96; 59.26; 40.84; 23.57; 16.41. Using reverse phase high resolution liquid chromatography it was found that tR (min) was 6.02 for the title compound under the conditions shown in the following table.

Preparation of Crystalline Form A The non-crystalline product E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamine] was dissolved] -quinazolin-6-yl.}. -alyl) -acetamide in boiling acetonitrile and then allowed to cool to room temperature with stirring. The solids were then filtered and washed with cold acetonitrile to produce a crystalline powder.

EXAMPLE 2 Crystalline Form B of E-2-Methoxy-N- (3-f4-3-methyl-4- (6-methy1-pyridin-3-yloxy-phenylamino-quinazoline) 6-yl-allyl) -acetamide The dimesylate salt of E-2-methoxy-N- (3- {4- [3-methyll-4- (6-methylpyrrn-3-) iloxj) -phenlamino] -quinazolin-6-yl.} -ali) -acetamide was prepared as follows: A 67.33 grams of the free base form E-2-methoxy-N- ( 3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -alyl) -acetamide (prepared in accordance with Example 1 above) in 400 ml of EtOH and 100 ml of CH2Cl2 at room temperature, a solution of 19.17 ml (2.05) equivs of methanesulfonic acid (CH3SO3H) in 100 ml of acetonitrile was added dropwise. it was suspended at room temperature for 15 minutes then the methylene chloride (-100 ml) was removed, an additional 600 ml of acetonitrile was added to complete the crystallization and the mixture was suspended for 2 hours.The crystals were filtered under a nitrogen atmosphere and washed with 100 ml of acetonitrile. The dimesylate salt (94.48 grams) was produced in a yield of 99%. The dimesylate salt produced according to the method of the preceding paragraph (90 g) was dissolved in water (-550 ml). Chloroform (-500 ml) was added to the solution followed by 1 N NaOH until a suspension / white precipitate (pH -13-14) was observed. The addition of chloroform before the NaOH reduced the gumming as the precipitate formed. The mixture was transferred to a separatory funnel (2 I) and the free base was extracted with three portions of chloroform (-300 ml). The extracts were combined (-1, 3 I), washed with water (-500 ml), dried with anhydrous magnesium sulfate and then filtered. The chloroform filtrate was concentrated in vacuo to provide a yellow amorphous solid / oil. This material was resuspended in ethyl acetate overnight resulting in a white solid. This material was then filtered, washed with cold ethyl acetate and then dried in a vacuum oven at 45 ° C to yield a white crystalline solid (-59 g). The free base was characterized by polarizing light microscopy (PLM), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). It is in the shape of a needle and indicates three endothermic tests by DSC (DSC melting points: 125 ° C, 160 ° C and 167 ° C) Example 3 Crystalline Form C of E-2-Methoxy-N- (3-f4-r3-methyl-4-yl-methyl-pyridin-3-yloxy) -phenylamino-1-aminopoly-6-yl) -alyl) -acetam Form C was prepared by combining Form B and methylene chloride and then concentrating to produce a foam. The foam was then suspended in acetonitrile for about three hours at room temperature and filtered to yield Form C. Example 4 Crystalline Form F of E-2-Methoxy-N-f3-f4-r3-methyl-4-f6-metH- pyridin-3-yloxy) -phenylamino-quinazolin-6-yl) -alyl) -acetamide Form F was prepared by combining Form B, as prepared in Example 2 and ethyl acetate to form a suspension. To this suspension, hydrogen peroxide (30%) and water were added and the resulting mixture was stirred overnight. The solids were isolated by filtration, rinsed with water and acetone and dried in vacuo at 40-45 ° C to produce Form F. Example 5 Form G crystalline de-2-methoxy-N- (3- {4-r3-methyl-4- (6-Methyl-pyridin-3-yloxy) -phenylamino-1-quinazolin-6-yl) -allyl) -acetamide Form G was prepared by forming a solution of free base (20 grams), formed according to the Example 1, methanol (10 ml) and methyltetrahydrofuran (90 ml) at 60 ° C. The solution was allowed to cool to room temperature and after reaching 23 ° C a suspension was formed. The solids were isolated by filtration and washed using methyltetrahydrofuran to produce Form G. Example 6 Crystalline form H of E-2-methoxy-N- (3- (4-r3Ht? Ethyl) - (6-methyl-pyridine-3- iloxn-phenylaminol-quinazolin-6-yl}. -alyl) -acetamide To a solution of E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl) -pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. -alyl) -acetamide in THF / hot acetone (5/100) were added two equivalents of succinic acid. After cooling overnight, the crystals were filtered and rinsed with acetone, The product was isolated as a white solid and verified as the sesquisuccinate complex of E-2-methoxy-N- (3). - { 4- [3-Methyl-4- (6-methy1-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. -alll) -acetamide by CHN analysis. = 61, 29; H = 5.61; N = 10.83; Experimental: C = 61, 04; H = 5.61; N = 10.85; The sesquisuccinate complex thus formed (5 grams) was mixed with water (25 ml) and chloroform (25 ml). To this mixture was added 1.1 equivalents of sodium hydroxide (aqueous 1 normal) and stirred until two layers had formed. The mixture was transferred to a separatory funnel and the layers were separated. The content of the funnel was mixed well and the layers were separated. The extraction was repeated a second time with an additional aliquot of chloroform (25 ml). The water layer was then discarded and the combined chloroform layers (-75 ml) were put back into the separatory funnel with some water (25 ml). The content of the funnel was mixed well and the layers were separated. The aqueous layer was discarded and the chloroform layer was placed in a single-neck flask. The chloroform was removed using rotary evaporation to produce a yellow oil. Ethyl acetate (125 ml) was added and stirred with the oil to produce a slurry. After stirring for about a day, the suspension was isolated via vacuum filtration using a Büchner funnel equipped with a filter paper (Whatman # 2). The solids were rinsed with ethyl acetate (25 ml) and then placed on a crystallization plate. The plate and solids were placed in a vacuum oven at 45 ° C to dry overnight to produce a pale yellow powder.

Claims (8)

1. A crystalline form of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. -alyl) -acetamide.

2. A crystalline form of E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -alil) -acetamide selected from the group consisting of: Form A, Form C, Form F, Form G and Form H.

3. A crystalline form according to claim 2, wherein said form is Form A, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows:

4. A crystalline form according to claim 2, wherein said form is selected from the group consisting of: (a) Form A, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-) theta), as follows: (b) Form A with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: 10 fifteen twenty (c) Form C with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (d) Form C, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (e) Form C, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (f) Form F, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (g) Form F, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (h) Form F, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (i) Form G, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (j) Form G, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (k) Form G, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: 10 15 20 (I) Form H, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (m) Form H, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows: (n) Form H, with an X-ray powder diffraction spectrum with characteristic maximum values, expressed in degrees (2-theta), as follows:

5. A crystalline form according to claim 2, wherein said form is Form A with a formula weight of 469.54; a crystal size of 0.24 mm x 0.08 mm x 0.06 mm, a monoclinic space group P21 (1) / n and unit cell dimensions: a = 9.456 A, b = 9.237 A, c = 27.947 A, a = 90 °, ß = 92.97 ° and y = 90 °. 6. A crystalline form according to claim 2, wherein said Form is Form A, characterized by nuclear magnetic resonance of solid-state C-13 with the following chemical shifts expressed in parts per million: 172.1; 158.6; 153.7; 149.6; 147.7; 138.8; 135.0; 132.4; 129.9; 125.8; 123.6; 120.9; 119.4; 118.4; 117.1; 71.3; 58.1; 44; 20.7 and 16.

6.

7. A composition comprising the crystalline form according to claim 1.

8. A pharmaceutical composition comprising the crystalline form according to claim 1.