MXPA00011311A

MXPA00011311A - Thermally stable trimetrexates and processes for producing the same

Info

Publication number: MXPA00011311A
Application number: MXPA/A/2000/011311A
Authority: MX
Inventors: Martin Stogniew; Ingomar Grafe; Johann Morsdorf
Original assignee: Us Bioscience Inc
Priority date: 1998-05-18
Filing date: 2000-11-17
Publication date: 2001-12-04

Abstract

The present invention provides for thermally stable forms of 2,4-diamino-5-methyl-6-[(3,4, 5-trimethoxyanilino)methyl]quinazoline, or trimetrexate. A crystalline 2,4-diamino-5-methyl-6-[(3, 4,5-trimethoxyanilino)methyl]quinazoline monohydrate, or trimetrexate monohydrate, belonging to the space group P1(#2) and having a triclinic cell with dimensions of about a=7.699Å, b=9.606Åand c=13.012Åis disclosed. A novel Schiff base compound, 2,4-diamino-5-methyl-6-[(3,4, 5-trimethoxyphenylimino)-methinyl]quinazoline, is also disclosed. The present invention further provides novel methods of producing stable trimetrexate free base compounds, including crystalline trimetrexate monohydrate. The crystalline monohydrate form provides increased stability over the anhydrous form.

Description

THERMALLY STABLE TRIMETREXATES AND PROCEDURES FOR THEIR PRODUCTION 1. FIELD OF THE INVENTION The present invention focuses on thermally stable forms of trimetrexate useful in pharmaceutical preparations. Particularly, the invention focuses on trimetrexate monohydrate and processes for its preparation, including a purified crystalline form. The trimetrexate monohydrate has an unexpectedly improved thermal stability compared to the anhydrous form and is therefore particularly useful as a bulk pharmaceutical substance and / or for the preparation of trimetrexate salts. 2. BACKGROUND OF THE INVENTION Trimetrexate, 2,4-diamino-5-methyl-6- [3,, 5-trimethoxyanilino) methyl] quinazoline is a useful pharmaceutical compound known to have antineoplastic, antiparasitic and antibacterial activity. The free base of trimetrexate has the structure: Trimetrexate is an inhibitor of dihydrofolate reductase (DHFR) which is known to catalyze the synthesis of DNA and RNA nucleotide precursors. Trimetrexate glucuronate is classified as a folate antagonist, and has been clinically evaluated and is now approved for use in the treatment of pneumonia caused by Pneumocystis carinii.

(PCP) in patients with acquired immunodeficiency syndrome (AIDS) (Physicians' Desk Reference, edition 51 (1997)). Inhibition of the DHFR enzyme results in the cellular depletion of reduced folates that are necessary for various cellular processes, including the synthesis of RNA and DNA, and ultimately results in cell death. It is this property that provides trimetrexate with its antineoplastic, antiparasitic and antibacterial activity. Trimetrexate has demonstrated antitumor activity against several lines of experimental murine and human tumor cells, in vitro and in vivo. For example, trimetrexate has been shown to exhibit anti-tumor activity against murine cell lines such as L1210, L5178Y, S-180, -256 in vitro. In addition, trimetrexate has shown antitumor activity against lines of human tumor cells derived from breast, colon, lung, or various cells, kidneys and melanoma, in vitro, in vivo studies have shown that trimetrexate has therapeutic utility against tumors of murines such as melanoma B16, tumors of colon 26 and 38, leukemia p388 and L1210 and breast cancer CD8F. Other possible uses of trimetrexate include the treatment of malaria, psoriasis, rheumatoid arthritis as well as prophylaxis against pneumonia caused by Pneumocystis 5 carinii. Trimetrexate as a free base is lipophilic, with very little solubility in water (less than 0.1 mg / mL). Several salts of trimetrexate with greater aqueous solubility are known. U.S. Patent No. 4,376,858 to Colbry ("Colbry") • 10 discloses trimetrexate glucuronate as a preferred salt, due to its greater solubility in water (more than 50 mg / mL), solubility and low glucuronic acid toxicity. Colbry also discloses a method to prepare trimetrexate glucuronate where trimetrexate and glucuronic acid are dissolved in ethyl acetate and hot methanol and the solution is then cooled to precipitate the glucuronate salt. Additional trimetrexate salts as well as • Methods for preparing them are described in PCT publication W096 / 21451. 20 Hicks et al., J. Labelled Compunds Radiopharm. , 29, 415 (1991), discloses another method of manufacturing a salt of trimetrexate glucuronate. In this method, trimetrexate and glucuronic acid are added to an aqueous solution in an ampoule. Followed by lyophilization to form a salt amorphous, solid.

Trimetrexate is available as a commercial drug product under the brand name Neutrexin® • (U.S. Biosciences). The pharmacological product was developed by Warner-Lambert / Parke-Davis as an injectable formulation presented in a flint glass bottle of 5 cc (USP type I) containing 25 mg of trimetrexate and 15.35 mg of D-glucuronic acid. Glucuronic acid is present in the formulation to help solubilize trimetrexate which is intrinsically insoluble in water. Neutrexin ® provides the Trimetrexate glucuronate in the form of a lyophilized powder, and reconstituted before use in combination with leucovorin for the treatment of pneumonia caused by severe Pneumocystis carinii in immunocompromised patients for example, patients suffering from AIDS (U.S. Bioscience's Neutrexin for PCP, Scripp 1886/87, 31 (1994)). The free base of trimetrexate of the prior art, hereinafter referred to as "trimetrexate", does not present • Stability during long-term storage, and degrades rapidly. To overcome the problem of In storage stability, trimetrexate is typically stored as a salt, due to the increased stability found for some trimetrexate salts. Stetson et al., J. Chromatography, 464, 163-171 (1989), comments on the stability of the glucuronate salt of trimetrexate obtained from Warner Lambert / Parke-Davis, Pharmaceutical Research Division (Pharmaceutical Research Division of Warner Lambert / Parke-Davis). This salt is apparently obtained from the process disclosed in the North American patent no. 4,376,858. Stetson indicates that the glucuronate salt has a half life in solution of 51.6 ± 0.8 days at a temperature of 37 ° C. The instability of trimetrexate creates numerous disadvantages. It is convenient to manufacture the trimetrexate in bulk and the final pharmaceutical formulation in different facilities to take advantage of the specialization of different manufacturing plants, and economies of production, shipping, packaging, storage and the like. However, the instability of the trimetrexate of the prior art makes it difficult to achieve these goals. In addition, the degradation of trimetrexate between the production and the final formulation negatively decreases the performance of the drug, and introduces additional costs in the manufacturing process necessary to produce a pharmaceutical grade product. Despite the disadvantages of trimetrexate, other non-salt, more stable forms of trimetrexate useful in pharmaceutical applications have not been identified. In fact, USAN and the USP dictionary of drug names' show trimetrexate only in two forms: the free base anhydrous (trimetrexate) and the trimetrexate glucuronate salt. Hempel et al., Cancer Biochem. Biophys., 10, 25-30 (1988) ("Hempel"), disclose molecular structures of crystalline trimetrexate acetate monohydrate. Hempel also identifies a free base of trimetrexate polyhydrate, characterized to a limited extent. In the Hempel document, the trimetrexate polyhydrate was crystallized from a DMSO methanol / water solution and characterized by x-ray diffraction. The crystals of trimetrexate polyhydrate belong to the space group C2 / c and have the following structural parameters a = 36.051A, b = 11.765Á, c = 10.623Á and ß = 105.69 °. The polyhydrate obtained by Hempel, however, has a limited characterization, its hydration number is unknown and consists of low quality crystals containing several disordered water molecules. Further. Hempel does not disclose any stability advantages of the trimetrexate polyhydrate form. Sutton et al., J. Med. Chem., 30, 1843-48 (1987) ("Sutton") reports the crystal structure of a trimetrexate DMSO-E0 adduct, trimethylrexate dimethylsulfoxide hydrate. Trimetrexate was crystallized as the DMSO hydrate, and the crystals were analyzed by x-ray diffraction. The crystals of the trimetrexate / DMSO-H2C adduct are triclinic, belonging to the spatial group P-l and having the following structural parameters: a = 9.423Á, b = 11.180Á, c = 12.399A and ß = 75.10 °. However, the only form of trimetrexate that was produced and analyzed was the DMSO-H20 adduct. In addition, Sutton does not disclose any advantages in regard to thermal stability of the adduct of DMSO-H20. A stable form other than trimetrexate salt has not been produced or previously characterized. It should be clear from the foregoing that there is a need for a bulk pharmaceutic substance of soluble trimetrexate which can be used to produce a final trimetrexate pharmaceutical product more efficiently and more economically. further, there is a need for an efficient and rapid synthesis for this stable bulk pharmaceutical substance. 3. COMPENDIUM OF THE INVENTION The present invention relates to novel forms which are not trimetrexate salts, such as for example trimetrexate monohydrate (TMH), which have improved thermal stability compared to the trimetrexate of the prior art. These stable forms, which are not salts, previously unknown, unexpectedly offer improved stability compared to other forms of trimetrexate, in storage and for oral and intravenous administration of the drug. In addition, trimetrexate monohydrate is non-hygroscopic and has favorable manufacturing characteristics, including good flow properties. The invention also embraces sterile forms of the monohydrate.

In its crystalline form, the preferred thermally stable trimetrexate TMH is characterized by a triclinic elementary cell, with dimensions of a = 7.699 A, b = 9.606 A, and c = 13.012 A, and belongs to the space group Pl (# 2). The identity and structure of TMH have been characterized by mass spectrometry, differential scanning calorimetry, thermal gravimetric analysis as well as x-ray crystallography at low temperatures. The present invention also offers novel chemical processes for producing trimetrexate monohydrate. In a preferred method, TMH is produced starting from the hydrated acetate salt. Briefly, the process includes: a. Prepare a crude trimetrexate by the treatment of trimetrexate acetate hydrate, with ammonia; b. Recrystallization of crude trimetrexate with dimethylformamide (DMF) to produce a pure trimetrexate-DMF adduct; c. The conversion of the trimetrexate-DMF adduct into trimetrexate hydrochloride by the formation of a trimetrexate gluconate intermediate by reaction with gluconic acid and removal of gluconate with acetic acid; and d. Formation of crystalline, pure TMH, by treatment of trimetrexate hydrochloride with ammonia. This procedure allows the conversion of existing supplies of the trimetrexate acetate hydrate salt into the stable trimetrexate monohydrate of the present invention: In another preferred method, TMH is produced by coupling quinazoline aldehyde with trimethoxyaniline through a Schiff base intermediate which, when reduced with sodium borohydride, provides trimetrexate monohydrate. This process includes the steps of: a. Produce a quinazoline aldehyde base by the format reaction of quinazoline aldehyde or quinazoline aldehyde diformate with ammonia; b. The coupling of the quinazoline aldehyde base with trimethoxyaniline to produce a quinazoline Schiff base; c. Reduction of the Schiff base of quinazoline in trimetrexate acetate hydrate by reaction with sodium borohydride; and d. Preparation of trimetrexate monohydrate from trimetrexate acetate hydrate through a 2-methoxypropanol adduct and purification of the TMH product. The Schiff base of quinazoline, 2, 4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyphenylimino) -methynyl] quinazoline, the trimetrexate-DMF adduct, and the trimetrexate 2-methoxypropanol adduct they are also novel compounds. Non-salt, thermally stable trimetrexates, trimetrexate monohydrate and quinazoline base Schiff base, and processes for their preparation or synthesis are described in more detail below. 4. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph of intensity versus diffraction angle for the x-ray diffraction of the crystalline trimetrexate monohydrate of the present invention. Figure 2 shows the structure of crystalline TMH as obtained from the data of x-ray crystallography.

Figure 3a shows the relative positions of trimetrexate molecules and their associated water molecules, within an elementary cell of crystalline TMH. Figure 3b shows the elementary cell of Figure 3a with light and shaded rotation to emphasize the atomic positions. The dotted lines show the intramolecular hydrogen bonding interactions within a single trimetrexate molecule, the intermolecular hydrogen bonding interactions between adjacent trimetrexate molecules, and the hydrogen bonding interactions between trimetrexate and water, within an elementary cell . Figure 4 shows the result of thermogravimetric analysis (TGA) for a sample of TMH. Figure 5 shows the result of differential scanning calorimetry (DSC) for the TMH sample.

Figure 6 shows a DSC-type scan of a TMH sample that has been heated to 180 ° C and then cooled to 25 ° C before obtaining this DSC data. Figure 7 is an HPLC chromatogram showing the relative stability of TMH as compared to anhydrous trimetrexate. The peaks at approximately 2 and 7 minutes and the large peak at approximately 20 minutes in the anhydrous sample indicate sample degradation. The structure and characteristics of UV light absorption of the degradation products that appears approximately at 20 minutes, 6-aminomethyl-5-methyl-2,4-quinazolindiamine, appear in example 6. 5. DETAILED DESCRIPTION OF THE INVENTION This invention represents, it is believed, the first disclosure, in a way that is not thermally stable salt of trimetrexate. Prior to this invention, trimetrexate was known to be thermally unstable in such a way that trimetrexate salt forms, such as trimetrexate glucuronate and trimetrexate acetate, were used in manufacturing and production. However, the description presented below refers to forms of trimetrexate which are not salts that are considered as thermally stable. Thus, the present invention is a thermally stable trimetrexate boat where trimetrexate is not a salt. Examples of thermally stable trimetrexate within the scope of the present invention are described below. 5.1 TRIMETREXATE MONQHYDRATE In one embodiment, the present invention offers a free base 5 of trimetrexate monohydrate (TMH) which exhibits improved stability compared to trimetrexate. In its crystalline form, TMH is characterized by the x-ray diffraction pattern shown in Figure 1. Figure 1 shows the normalized relative intensity of versus 2?, For # 10 X-ray diffraction of an individual TMH crystal at a temperature of -175 ° C, using Mo-a radiation. The procedure for obtaining this diffraction pattern is described in detail in Example 1, below. Figure 2 shows the molecular structure of the form crystalline TMH. The atoms in Figure 2 are numbered to correspond to the data presented in Tables 2-4 of Example 1. As shown in the figure, the molecule of • trimetrexate is associated with a water molecule in a well-defined position relative to trimetrexate, close of the amino group in the 2-position (N3) of the heterocyclic ring. The atoms that form the quinazoline ring define a plane that has a dihedral angle of approximately 107.5 ° relative to the plane containing the trimethoxyanilino group (see Table 5). 25 The crystalline trimetrexate monohydrate belongs to the space group Pl (# 2) and is crystallized in a triclinic elementary cell of dimensions: a = 7.699 (2) A a = 77.702 (8) ° b = 9.606 (3) A ß = 85.529 (4) ° c = 13.012 (3) A? = 83.600 (4) ° d = 932.9 (4) A Figure 3a shows the relative positions of two trimetrexate molecules and several associated water molecules, within an elementary TMH cell. Figure 3b shows the elementary cell of figure 3a with light and shaded rotation to show the atomic positions. The dotted lines in Figure 3b indicate hydrogen bonding interactions. As is clear from the figure (see also Table 6), TMH is characterized by intermolecular hydrogen bonding interactions between adjacent trimetrexate molecules within the TMH crystal, intramolecular hydrogen bonding interactions within an individual trimetrexate molecule, and in hydrogen bond between trimetrexate and associated water molecules nearby. This high degree of hydrogen bonding probably contributes to the surprising and unexpected stability of TMH as compared to the less stable trimetrexate. The discovery of this thermally stable trimetrexate is especially important for the pharmaceutical industry, since this material can easily be used to prepare pharmaceutical salt (s) of trimetrexate which is used to treat various disorders, in accordance with described above. 5.2 METHOD FOR THE PRODUCTION OF TRIMETREXATE MONOHYDRATE FROM TRIMETREXATE ACETATE HYDRATE SALT The present invention also encompasses methods for the production of trimetrexate monohydrate. The trimetrexate previously synthesized by known methods was frequently converted into a salt such as acetate due to its instability. The present invention provides a method for producing the more stable monoether form of trimetrexate starting from the crude or purified acetate salt. The trimetrexate acetate salt can be converted to pure trimetrexate monohydrate according to the process described below and known as Scheme 1. A detailed example of the synthesis according to Scheme 1 appears in the following examples. In one step of the TMH production, the crude salt of trimetrexate acetate is converted to crude trimetrexate by removal of the associated acetate molecule, as shown in step 1: Step 1 The starting material, crude trimetrexate trimetrexate acetate, does not need to be of particular purity to produce a pharmaceutical grade, high purity TMH product. Particularly, trimetrexate acetate can contain significant amounts of degradation product and still be suitable for use in the method of the present invention. In step 1, the trimetrexate acetate is dissolved in a polar solvent or a mixture of solvents such as for example an aqueous alcohol solvent, preferably a mixture of n-butanol and water, and more preferably a mixture of n-butanol and water in a ratio of approximately 10: 1, a ratio of about 4: 1 being especially preferred. A base, preferably aqueous ammonia, is added to react with the acetate resulting in the loss of ammonium acetate. Preferably, a small catalytic amount of sodium metabisulfite is also added. Auxiliary agents such as Tonsil (bentonite) and Supercel can also be added. The reaction is facilitated by heating the solution to mild reflux, preferably at a temperature of about 90 ° C, and with stirring for about 10 minutes. The mixture is then filtered, then heated to a temperature of about 70 ° C and ammonia is added. The raw trimetrexate base which is crystallized is then washed with a polar solvent such as water or alcohol, preferably a mixture of water and ethanol. In another step, the crude base of trimetrexate is converted into an adduct of pure dimethylformamide (DMF). Step 2 The raw trimetrexate base is dissolved in a mixture of DMF and water, preferably a volume / volume ratio of about 10: 1. The solution is initially heated to a temperature of about 100 ° C, then a polar component is added, for example an alcohol, preferably ethanol, with which it is called ssooliuucci-óunn at a temperature of about 55-60 ° C at which crystallization occurs. The resulting crystals are then washed with ethanol to provide a pure trimetrexate-DMF adduct. This trimetrexate-DMF adduct itself is a novel compound and is included within the scope of the invention. In another step, the DMF adduct is converted to trimetrexate hydrochloride, through a trimetrexate gluconate intermediate. Step 3 The gluconate is easily formed by suspending the adduct of DMF in hot water, and by adding a gluconate source such as gluconic acid. Preferably, Supercel-g and a small amount of activated carbon are also added. The mixture is stirred at a temperature of about 50 ° C for about 10 minutes, and filtered. The hydrochloride salt can be formed by the reaction of the gluconate with a suitable acid, such as for example acetic acid, and by stirring at a temperature of about 50 ° C for about 10 minutes with an aqueous sodium chloride solution. The resulting crystals can be filtered and washed with water or alcohol, preferably ethanol, or mixtures thereof to provide the salt of trimetrexate hydrochloride. Finally, in a last step, the trimetrexate hydrochloride salt is converted to the pure trimetrexate monohydrate. Step 4 The reaction is carried out in a polar solvent or in a mixture of solvents, at a temperature of about 80 ° C. Suitable solvents include various alcohols well known to those skilled in the art because they are miscible with the water. Preferably, the solvent is a mixture of water and n-butanol, and most of the solvent is water; a preferred ratio is about 3: 1. The addition of a base precipitates trimetrexate monohydrate, the base ^^ can be an organic amine soluble in water, for example trimethylamine or ethanolamine, or preferably ammonia. The precipitated trimetrexate monohydrate can be filtered, washed (ethanol / water) and dried in vacuum, and optionally sterilized. The TMH obtained in this way can be optionally sieving and mixing, as desired. 5.3. METHOD FOR THE PRODUCTION OF TRIMETREXATE MONOHYDRATE fl | FROM QUINAZOLINE ALDEHYDE FORMAT OR DIFFORMATO The present invention also encompasses a method for the production of TMH starting from format or diformate. of quinazoline aldehyde, in accordance with the process described below and known as Scheme 2. A detailed example of a synthesis according to Scheme 2a appears in the examples presented below. In one step of the process, the aldehyde format or diformate of The quinazoline is converted to carboxaldehyde hydrate of 2,4-diamino-5-methyl-6-quinazoline (quinazoline aldehyde base). Step 1 The initial material, format or quinazoline aldehyde diformate can be synthesized by reduction of the corresponding nitrile, 2,4-diamino-5-methyl-6-quinazoline carbonitrile, with Raney nickel and formic acid (see Biochem. Pharmacology, 33 , 3251 (1984), which is incorporated herein by reference). The quinazoline aldehyde format or diformate is dissolved in a polar solvent or a mixture of solvents such as for example an aqueous alcohol solvent, preferably a mixture of n-butanol and water, in a ratio of about 1: 5: 1. The free aldehyde base is obtained by stirring the solution at a gentle reflux temperature for about 90 ° C for about 20 minutes, in the presence of triethylamine, ammonia and a small amount of ethylenediaminetetraacetic acid (EDTA). The resulting crystals are filtered and washed with alcohol and water, preferably n-butanol. The crystals may optionally be repeatedly washed with different alcohols, or water or mixture thereof. Preferably, n-butanol, ethanol and then water are used. In another step, the quinazoline aldehyde is coupled with trimethoxyaniline to produce 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyphenylimino) -methynyl] quinazoline (quinazoline Schiff's base). Step 2 The solvent is preferably a mixture of an aliphatic alcohol that forms an azeotrope with water, and a hydrocarbon. Suitable alcohols include, but are not limited to, n-butanol, and suitable hydrocarbons include, but are not limited to, toluene, xylene or chlorobenzene. Preferably, the solvent is a mixture of n-butanol and toluene in a ratio of about 5: 1. The reaction is conveniently carried out by heating the wet base of quinazoline aldehyde in the alcohol / toluene solvent to an azeotropic site, and by distillation of dehydration water. When n-butanol and toluene are employed in a ratio of 5: 1, the distillation temperature varies from about 89 ° C initially to about 110 ° C (liquid phase temperature). The resulting Schiff kiss can be removed by filtration, and washed with alcohol, preferably n-butanol, and an ether, preferably t-butyl methyl ether. In another step, the Schiff base of quinazoline is reduced in trimetrexate and precipitated as the acetate salt. Step 3 The Schiff base is easily hydrolyzed, in such a way that the reduction has to be carried out immediately after step 2. The solvent employed is preferably a mixture of tetrahydrofuran (THF) and water in a proportion of about 4: 1. However, other ethers known to those skilled in the art, such as for example 1,4-dioxane, can also be used. Sodium carbonate, trimethoxyaniline and quinazoline Schiff base are heated to a temperature of about 45 ° C, and an aqueous solution of sodium borohydride is slowly added over several hours while the reaction is maintained under hydrogen protection. After finishing the reduction, most of the THF can be removed by distillation (approximately 90%), and an alcohol-water mixture is added. Various alcohols known to those skilled in the art may be used, but the alcohol selected must not be completely miscible with water. Suitable alcohols include isobutanol and n-butanol. Preferably, a mixture of n-butanol and water is used in a 2: 1 ratio. The mixture can be filtered and washed with water to provide a crude trimetrexate base. The acetate salt is formed by suspending the crude kiss in a polar solvent such as an ethanol / water mixture, heating to about 70 ° C, adding lactic acid and acetic acid, and mixing the solution with Tonsil and a small amount of activated carbon. The filtrate is mixed with sodium acetate and acetic acid for about 30 minutes at a temperature of 70-75 ° C, and then cooled to a temperature of 20 ° C, filtered and washed with acetic acid. Finally, the pure TMH product is formed from the acetate salt. Step 4 The trimetrexate acetate is first converted to an adduct of 2-methoxypropanol, and then recrystallized as the free base. The 2-methoxypropanol adduct of trimetrexate itself is a novel compound included within the scope of the present invention. The product of trimetrexate monohydrate is dried in vacuum (at a temperature of 40-80 ° C, preferably of about 50 ° C, for 2-40 hours, preferably of about 4-8 hours), and optionally sieved, mixed and sterilized. 5.4. QUINAZOLINE SCHIFF BASE The present invention also features the novel chemical compound having the formula This compound, 2,4-dzamino-5-methyl-6- [3,4,5-trimethoxyphenylimino) -methynyl] quinazoline (Schiff's base of quinazoline) is produced by the method shown above in Scheme 2. The Schiff base of quinazoline is a yellow powder with a molecular formula Ci9H2: Ns03 and a formula weight of 367.41 g / mol. The characterization of this compound is described in the examples that we present below. In the following working examples, certain embodiments of the present invention are illustrated, without having a • limiting character. 6. EXAMPLES 6.1. EXAMPLE 1; X-RAY CRYSTALOGRAPHY OF TMH 20 The crystal molecular structure of crystalline trimetrexate monohydrate was determined by x-ray diffraction. Crystal evaluation, elemental cell determination, and data collection using Moa radiation at a temperature of -175 ° C were performed.

Preliminary analysis of elementary cell constants indicated a triclinic elementary cell. Intensity statistics obtained during the data collection indicated the presence of a centrosymmetric space group 16 that suggests the spatial group P-1. The structure was solved by direct methods. All atoms that were not hydrogen were initially refined using isotropic and then anisotropic temperature factors. Redundant data were averaged, providing a Rav of 0.065. The hydrogen atoms were located by examining a map of electron density differences, but they were not refined. After the addition of hydrogen atoms, three additional cycles of complete matrix refining were carried out. Data collection A clear needle crystal of C? 9H23? 3N5"H20 having approximate dimensions of 0.13 x 0.15 x 0.40 mm was mounted on a fiberglass All measurements were made on a Quantum CCD area detector connected to a Rigaku AFC7 diffractometer with monochrome graphite Mo-Ka radiation The cell constants and an orientation matrix for data collection corresponded to a primitive triclinic cell with dimensions: a = 7.699 (2) A a = 77.702 (8) ° b = 9.606 (3) A ß = 85.529 (4) ° c = 13.012 (3) A? = 83.600 (4) ° d = 932.9 (4) A3 For Z = 2 and a formula weight of 387.44, the density calculated is of 1.38 g / cm3 Based on a statistical analysis of intensity distribution, and the successful refinement of the structure, the spatial group was determined as Pl (# 2) .The data was collected at a temperature of -175 ± 1 ° C to a value 2? Maximum of 58.5 ° .The data was collected • 10 in oscillations of 0.50 ° with exposures of 98.0 seconds. A data sweep was performed using oscillations f from 0.0 to 190 °, and? = 0 and a second sweep was performed using? oscillations between -17.0 and 23.0 ° a? = 90.0. The distance from glass to detector was 38.60 mm. The angle of detector displacement was -5.00 °. Data reduction Of the 7355 reflections that were collected, 3379 were • unique (Rint = 0.065); equivalent reflections were combined. The linear absorption coefficient, μ, for Mo-Ka radiation is 1.0 cm ~~. The data was corrected for Lorentz effects and polarization. A correction for secondary extinction was applied (coefficient = 1.54877 x 10"6). 'Solution and structure refinement The structure was solved by direct methods (SAPI91: Fan Hai-Fu (1991): Structure Analysis Program with Intelligent Control (Intelligent Control Structures Analysis Programs), Rigaku Corporation, Tokyo, Japan). The atoms that were not hydrogen were refined in a way • anisotropic. Hydrogen atoms were included but not refined. The final full-matrix least squares refinement cycle was based on 1537 observed reflections (I> 3.00s (I)) and 254 variable parameters and convergence (the largest parameter displacement was 0.02 times its ESD) with concordance factors do not • 10 weighted of: R = S | | Fo | - | F0 | l /? IFol = 0.049 Rw = [Sw (| Fo | - | Fc |) 2 /? Fo2] 1 2 The standard deviation of a unit weight observation, defined by function 15 [Sw (| Fo | - | Fc |) 2 / (No-Nv)] 1 2 where N0 and Nv are the number of observations and the number of variables, respectively, was 2.41. The scheme of • weighting was based on counting statistics and included a factor (p = 0.040) to decrease the weight of the reflections intense. Graphs of? W (| F01 - I Fc |) 2 versus I F0 I, reflection order in data collection without? /? and several kinds of indexes did not show surprising trends. The maximum and minimum peaks on the Fourier final differential map corresponded to 0.31 and -0.37 e ~ / A3, respectively. 25 Neutral atom scattering factors were taken from Cromer and Weber (International Tables for X-ray Crystallography, volume IV, The Kynoch Press, Birmingham, England, Table 2.2A (1974)). Abnormal effects of dispersion were included in Fca? C (Ibers, J.A. &; Hamilton, W.C .; Acta Crystallogr. , 17, 781 (1964)); the values for Df and Of "were the values of Creagh and McAuley (International Tables for Crystallography, Vol. C, (AJC Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992) The values for the mass attenuation coefficients are the values of Creagh and Hubbell (International Tables for Crystallography, Vol. C, (A.J.C.

Wilson, ed.), • Kluwer Academic Publishers, Boston, Table 4. 2.4.3, pages 200-206 (1992)). All calculations were made using the teXsan crystallographic programmatic package (teXsan for Windows: crystal structure analysis package, Molecular Structure Corporation (1997)). The details of the experiment are summarized in Table 1. The atomic positions, link lengths, link angles, least squares planes, as well as hydrogen bond distance and hydrogen bond angles appear in Table 2-6. Table 1: X-ray Diffraction Analysis of TMH A. Glass data Empirical formula C? 9H2? N503 Formula weight 387.44 Glass color, clear habit, needle Glass dimensions 0.13 x 0.15 x 0.40 mm Triclinic crystal system Type of crystal reticulate Primitive Cross-linking parameters a = 7.699 (2) A b = 9.606 (3) A c = 13.012 (3) A a = 77.702 (8) ° ß = 85.529 (4) °? = 83.600 (4) ° v = 932.9 (4) A3 Space group Pl (# 2) Value of Z 2 Dcalc 1,379 g / cm3 Fooo 412.00 (MoKa) 0.99cm 1 B. Measurements of intensity Diffractometer Quantum CCD / Rigaku AFC7 Radiation MoKa (? = 0.71069 A) graphite monochrome Detector aperture 81.466 mm x 81.466 mm Data images 460 Exposures at 98.0 seconds Oscillation range of f 0.0 - 190.0 ° (? = 0) Oscillation range of? -17.0 - 23.0 ° (? = 90.0) Detector position 38.60 mm Oscillating angle -5.00 ° of detector Z £%? Ax 58.5 ° Reflections no. Total: 7355 measurements Unique: 3379 (R? Nt = 0.065) Corrections Lorentz polarization Secondary extinction (coef: 1.54877e-06) C. Solution and refinement of structures Structure solution Direct methods Refinement Least squares of complete matrices Minimized function? (| F: | - | Fc |) 2 Weights of least squares w = i 0¿ (FO) Factor p 0.0400 Abnormal dispersion All atoms other than hydrogen No. of observations 1537 (I> 3.00s (I) No of variables 254 Relationship between reflection 6.05 and parameter Residues: R; R 0.049; 0.033 Goodness of adjustment indicator 2.41 Final displacement cycle 0.02 max / error Peak max in difference map 0.31 e "/ A: final Minimum peak in difference map -0.37 e" / final A3 Table 2: Atomic coordinates and Biso / Beq in TMH Atom X and Beq 0 (1) 0.3653 (3) 0.9624 (3) 0.1127 (2) 1.17 (8) 0 (2) 0.1577 (3) 0.8262 (3) 0.0178 (2) 1.20 (8) 0 (3) 0.2013 (3) 0.5439 (3) 0.0392 (2) 1.34 (9) 0 (4) 1.1580 (4) -0.2362 (3) 0.8075 (2) 1.81 (9) N (l) 1.2983 (4) 0.1235 (4) 0.5061 (3) 1.89 (10) N (2) 1.0957 (4) 0.0206 (4) 0.6443 (3) 1.03 (10) N (3) 1.3742 (4) -0.0874 (4) 0.6222 (3) 1.33 (10) N (4) 0.8211 (4) 0.1176 (4) 0.6715 (3) 1.71 (10) N (5) 0.6829 (4) 0.5050 (4) 0.2626 (3) 1.23 (10) C (l) 1.2527 (5) 0.0245 (5) 0.5870 (4) 1.08 (13) C (2) 1.1687 (5) 0.2310 (5) 0.4704 (4) 0.92 (12) C (3) 1.2149 (5) 0.3367 (5) 0.3840 (3) 1.13 (12) C (4) 1.0900 (5) 0.4438 (5) 0.3421 (3) 0.94 (12) C (5) 0.9155 (5) 0.4463 (5) 0.3852 (4) 0.79 (12) C (6) 0.8662 (5) 0.3457 (5) 0.4705 (3) 0.78 (12) C (7) 0.9962 (5) 0.2337 (5) 0.5175 (3) 0.69 (12) C (8) 0.9714 (5) 0.1243 (5) 0.6105 (4) 0.98 (12) C (9) 0.6752 (5) 0.3496 (5) 0.5119 (3) 1.25 (12) C (10) 0.7883 (5) 0.5662 (5) 0.3280 (4) 1.14 (12) C (ll) 0.5557 (5) 0.5905 (5) 0.1999 (3) 1.00 (12) C (12) 0.5334 (5) 0.7388 (5) 0.1905 (3) 0.93 (12) C (13) 0.4006 (5) 0.8162 (5) 0.1280 (3) 0.72 (12) C (14) 0.2912 (5) 0.7471 (5) 0.0790 (3) 0.77 (12) C (15) 0.3185 (5) 0.6005 (5) 0.0892 (3) 0.92 (13) C (16) 0.4511 (5) 0.5186 (5) 0.1488 (3) 0.90 (12) C (17) 0.4975 (5) 1.0382 (5) 0.1445 (4) 1.43 (12) C (18) -0.0087 (5) 0.8361 (5) 0.0785 (4) 1.54 (13) C (19) 0.2096 (5) 0.3909 (5) 0.0545 (4) 1.3 (13) H (l) 1.3375 -0.1703 0.6761 1.9640 H (2) 1.4773 -0.0888 0.5781 1.9640 H (3) 1.3531 0.3345 0.3602 1.9640 H (4) 1.1199 0.5349 0.2755 1.9640 H (5) 0.6080 0.4232 0.4522 1.9640 H (6) 0.6514 0.3589 0.5731 1.9640 H (7) 0.6367 0.2424 0.5355 1.9640 H { 8) 0.7338 0.1995 0.6536 1.9640 H (9) 0.8203 0.0598 0.7348 1.9640 H (10) 0.6884 0.5991 0.3816 1.9640 H (ll) 0.8411 0.6672 0.2910 1.9640 H (12) 0.7357 0.3999 0.2501 1.9640 H (13) 0.6189 0.7960 0.2269 1.9640 H (14) 0.4926 1.0191 0.2280 1.9640 H (15) 0.6317 1.0242 0.1025 1.9640 H (16) 0.4502 1.1480 0.1195 1.9640 H (17) -0.0003 0.9006 0.1312 1.9640 H (18) -0.0391 0.7260 0.1209 1.9640 H (19) -0.0917 0.8909 0.0234 1.9640 H (20) 0.0927 0.3764 0.0101 1.9640 H (21) 0.3437 0.3439 0.0222 1.9640 H (22) 0.2070 0.3387 0.1297 1.9640 H (23) 0.4873 0.40006 0.1493 1.9640 H (24) 1.1678 -0.1587 0.7529 1.9640 H (25) 1.1230 -0.2322 0.8724 1.9640 Beq = (8/3) p2 (One (aa +) 2 + U22 (bb +) 2 + U33 (cc + ) 2 + 2U? 2aa + bb + gamma eos + 2U23aa + cc + cosß + 2U23bb + cc + thing) Table 3: Link lengths (A) in TMK Atom atom distance 0 (1) C (13) 1.375 (5) 0 (2) C (14) 1,402 (4) 0 (3) C (15) 1,372 (5) 0 (4) H (24) 0.92 N (l) C (l) 1.315 (5) N (2) C (l) 1.370 (5) N (3) C (l) 1,368 (5) N (3) H (2) 0.94 N (4) H (8) 0.98 N (5) C (10) 1.467 (5) N (5) H (12) 1.09 C (2) C (7) 1.418 (5) C (3) H (3) 1.08 C (4) H (4) 1.12 C (5) C (10) 1.529 (5) C (6) C (9) 1.526 (5) C (9) H (5) 1.06 C (9) H (7) 1.08 C (10) H (ll) 1.09 C (ll) C (16) 1,404 (6) C (12) H (13) 1.10 C (14) C (15) 1.380 (6) C (16) H (23) 1.14 C (17) H (15) 1.14 C (18) H (17) 1.03 C (18) H (19) 1.02 C (19) H (21) 1.16 0 (1) C (17) 1,449 (5) 0 (2) C (18) 1,457 (5) 0 (3) C (19) 1.436 (5) 0 (4) H (25) 0.87 N (l) C (2) 1,385 (5) N (2) 'C (8) 1.330 (5) N (3) H (l) 0.99 N (4) C (8) 1,351 (5) N { 4) H (9) 0.89 N (5) C (ll) 1,400 (5) C (2) C (3) 1,398 (6) C (3) C (4) 1.380 (6) C (4) C (5) 1.415 (5) C (5) C (6) 1,367 (6) C (6) C (7) 1,452 (5) C (7) C (8) 1.440 (6) C (9) H (6) 0.93 C (10) H (10) 1.07 C (ll) C (12) 1.395 (6) C (12) C (13) 1,400 (5) C (13) C (14) 1.395 (6) C (15) C (16) 1.395 (5) C (17) H (14) 1.06 C (17) H (16) 1.07 C (18) H (18) 1.12 C (19) H (20) 1.14 C (19) H (22) 1.00 Table 4: Bonding angles (°) in TMH Atom atom atom angle C13 01 C17 115.9 (3) 5 C15 03 C19 117.8 (3) Cl NI C2 116.0 (4) Cl N3 Hl 119.4 Hl N3 H2 124.8 C8 N4 H9 119.4 • 10 CIO N5 CU 121.2 (4) CU N5 H12 122.4 NI Cl N3 118.2 (4) NI C2 C3 116.6 (4) C3 C2 C7 121.2 (4) 15 C2 C3 H3 116.0 C3 C4 C5 120.6 (5) C5 C4 H4 116.3 • C4 C5 CÍO 115.2 (4) C5 C6 C7 119.1 (4) 20 C7 C6 C9 121.2 (4) C2 C7 C8 114.9 (4) N2 C8 N4 113.8 (4) N4 C8 C7 123.5 (4) C6 C9 H6 115.1 25 H5 C9 H6 106.0 H6 C9 H7 103.1 N5 CIO H10 100.0 C5 CIO H10 110.7 H10 CIO Hll 102.3 N5 CU C16 116.3 (4) CU C12 C13 117.9 (4) C13 C12 H13 119.6 01 C13 C14 115.5 (4) 02 C14 C13 120.3 (4) C13 C14 C15 119.4 (4) 03 C15 C16 123.9 (5) CU C16 C15 117.7 (4) C15 C16 H23 122.7 (4) 01 C17 H15 114.6 H14 C17 H15 117.2 H15 C17 H16 106.2 02 C18 H18 109.5 H17 C18 H18 110.7 H18 C18 H19 117.7 03 C19 H21 111.0 H20 C19 H21 114.1 H21 C19 H22 101.6 C14 02 C18 112.1 (3) H24 04 H25 125.6 Cl N2 C8 116.4 (4) Cl N3 H2 113.5 C8"N4 H8 115.1 H8 N4 H9 122.1 CIO N5 C12 114.2 NI Cl N2 127.5 (4) N2 Cl N3 114.3 (4) NI C2 C7 122.2 (4) C2 C3 C4 119.5 (4) C4 C3 H3 124.2 C3 C4 H4 123.1 C4 C5 C6 121.4 (4) C6 C5 CIO 123.4 (4) C5 C6 C9 119.7 (4) C2 C7 C6 118.2 (4) C6 C7 C8 126.9 (4) N2 C8 C7 122.7 (4) C6 C9 H5 104.0 C6 C9 H7 110.1 H5 C9 H7 119.0 N5 CIO C5 108. (4) N5 CIO Hll. 116.6 C5 CIO Hll 117.2 N5 CU C12 121.5 (4) C12 CU C16 122.2 (4) CU C12 H13 122.5 01 C13 C12 123.4 (4) C12 C13 C14 121.1 (4) 02 C14 C15 120.3 (4) 03 C15 C14 114.3 (4) 5 C14 C15 C16 121.7 (4) CU C16 H23 119.2 01 C17 H14 108.6 01 C17 H16 103.3 H14 C17 H16 105.5 • 10 02 C18 H17 108.9 02 C18 H19 102.6 H17 C18 H19 106.9 03 C19 H20 101.8 03 C19 H22 115.0 15 H20 C19 H22 113.9 Table 5: Least squares planes in TMH Plane of quinazoline Plane of trimethoxyanilin • Atom Distance Atom Distance NI -0. .022 (4) CU -0.007 (4) N2 0. .022 (4) C12 -0.004 (4) Cl -0. , 059 (4) C13 0.013 (4) C2 0., 012 (4) C14 -0.010 (4) C3 0. .045 (5) C15 0.000 (4) C4 0, .030 (4) C16 0.012 (5) C5 -0, .034 (4) C6 -0.051 (4) C7 -0.005 (4) • C8 0.064 (4) Statistics Plane Mean deviation X2 Quinazoline 0.0345 809.4 Trimethylaniline 0.0077 25.4 Dihedral angle Between planes: 107.52 ° • 10 Table 6: Hydrogen binding interactions in TMH AHB AH (A) H ... B (A) A ..B (A) AH ... B (°) 04 H24 N2 0.92 2.04 2.913 (5) 159.4 04 H25 02 0.87 2.13 2.923 (4) 151.0 N3 H2 NI 0.94 2.01 2.943 (5) 171.3 15 N5 H12 04 1.09 1.96 3.021 (5) 166.0 N3 H2 N2 0.94 3.13 2.300 (4) 114.1 6.2 EXAMPLE 2: ELEMENTAL ANALYSIS OF TMH Two samples of trimetrexate monohydrate were analyzed to determine the content of carbon, hydrogen and nitrogen. The results for both samples are shown in Table 7. Trimetrexate monohydrate, C? 9H23? 3 5'H 0 has a molecular weight of 387.44 g / mol. The theoretical values presented in table 7 are based on the elemental composition of the monohydrate. The data shows a good correspondence with the expected results for the monohydrate. Table 7. Elemental analysis of C, H and N in TMH Element Sample 1 (%) Sample 2 (%) Theoretical (%) Carbon 59.14 59.08 58.90 Hydrogen 6.55 6.63 6.50- Nitrogen 18.04 18.22 18.08 6.3 EXAMPLE 3: MASS SPECTROMETRY They were taken mass spectra of two samples of trimetrexate monohydrate. The spectra were measured with a Hewlett-Packard 5989A MS Engine mass spectrometer with a hyperbolic quadrupole mass filter. The ionization method was direct impact of electrons, at an ionization energy of 70 eV. The probe was programmed from 45 ° C to 250 ° C at a speed of 25 ° C / min. The mass spectra for the two samples were equivalent. Both the molecular ion and the base ion m / z = 187 (M + minus the trimethoxyanilino moiety) were clearly present. The major fragment ions observed, their relative intensities and the assigned identities appear in table 8. Table 8. Mass spectrometry data M / z Relative abundance (%) Identity 369. 11 M + 187 100 M + - TMA 183 14 TMA'H + 170 17 m / z 187 - NH3 168 16 TMA.H + - CH3 TMA = Trimetrexate 3, 4, 5-trimethoxyaniline portion 6.4 EXAMPLE 4: THERMOGRAVIMETRIC ANALYSIS Two samples of trimetrexate monohydrate were analyzed using a DuPont 951 TGA module and an Instruments Thermal Analyst 2000 interface. The data was analyzed with the programmatic DuPont TGA v5.14A. Each of the samples analyzed had a size between 5 and 6 mg. In order to ensure that the instrument analyzed the samples of that size with precision, a control experiment was carried out with the sulfaguanidine standard.

(Sigma) Sulfaguanidine has a theoretical loss of volatiles of 7.5%. In the control experiment, a sulphaguanidine sample of 6.0870 mg was used. The sample was heated from 25 ° C to 150 ° C with an increase of 5 ° C / min, with a nitrogen flow rate of 50 cc / min. A loss of volatiles of 7,837% was observed, which corresponds to a positive error of approximately 4.5%. Two samples of TMH were subsequently analyzed, under the same experimental conditions as in the case of the control experiment with sulfaguanidine, except that the temperature range was extended to approximately 210 ° C. A sample of 5.5440 mg of TMH showed a loss of substances volatiles of 0.2601 mg or 4.692%, and a sample of 5.4350 mg showed a loss of 0.2578 mg, or 4.743%. The theoretical loss of volatile substances for TMH is 4.65%. The TGA curve obtained for one of the two TMH samples (the 5.5440 mg sample) is shown in Figure 4. Two additional samples of TMH were analyzed, using a DuPont 1090 thermal analyzer operating with a programmatic TGA analysis. V2.0 Heavy samples with precision of similar weight were heated from 25 ° C to 200 ° C with an increase of 10 ° C / min. The two samples presented losses of 4.57% and 4.56%. 6.5 EXAMPLE 5: DIFFERENTIAL EXPLORATION CALORIMETRY Two additional samples of TMH were analyzed, using a DuPont 1090 thermal analyzer operating with a programmatic Interactive DSC V3.0. Heavy samples with precision of similar weight were heated from 25 ° C to 300 ° C with an increase of 10 ° C / min. The DSC scan for one of the two samples is shown in Figure 5. Two endotherms were observed for each sample, at similar temperatures, as shown below: Endotherm Sample 1 Sample 2 First 166.5 - 172.3 ° C 159.9 - 169.9 ° C Second 216.4 - 219.8 ° C 217.5 - 220.7 ° C The first endotherm is consistent with the loss of water from the crystal matrix, and the second endotherm is fusion.

This conclusion was verified through the visual observation of samples heated in a similar manner with a Buchi melting point apparatus. Within the temperature range of 160-175 ° C, no fusion or "wetting" of the samples was observed. It was observed that sample 1 melted at a temperature of 219.5 to 222.5 ° C, and sample 2 melted at 218.5 to 221.5 ° C. The thermal behavior of trimetrexate monohydrate was further investigated using a different heating pattern. Samples were heated beyond the first endotherm (at 180 ° C), cooled, and then heated again from 25 ° C to 230 ° C. In the second heating cycle, only one endotherm was observed at approximately 220 - 221 ° C. This result is consistent with the loss of water during the first heating cycle. Once the water in the glass is boiled during the first heating cycle, it can not be reassociated with the trimetrexate molecules in the same way. Accordingly, the second heating cycle shows only a single endotherm corresponding to the melting. The sample DSC footprint in Figure 6. 6.6 EXAMPLE 6: THERMAL STABILITY OF TMH COMPARED TO TRIMETREXATE ANHYDRO Samples of trimetrexate monohydrate and anhydrous trimetrexate were analyzed to compare the thermal stability of anhydrous trimetrexate with the thermal stability of the monohydrate of trimetrexate of the present invention. • Trimetrexate Anhydrate Anhydrous trimetrexate was prepared by dehydration of trimetrexate monohydrate. A sample of trimetrexate monohydrate (approximately 30 g) was placed in a Petri dish and dried in a vacuum desiccator in phosphorus pentoxide. The sample was dried at a pressure of approximately 100 microns for 6 days. 10 Test procedure The following procedure was used to test the purity of samples of trimetrexate monohydrate and anhydrous trimetrexate. Samples of the compounds were analyzed by HPLC. 15 The mobile phase is prepared by first dissolving 5 g of sodium dodecyl sulfate (Aldrich 86, 201-0 or equivalents) in 1100 mL of water and adjusting the pH to 3 with glacial acetic acid (approximately 5 mL). 825 mL of HPLC grade acetonitrile were then added, and the solution was completely mixed, avoiding excessive foam formation. The unfiltered solution is then degassed by sonication for 5 minutes. The solution is degassed immediately before use, and at the beginning of each day. Standard solutions are prepared in duplicate with a reference compound of trimetrexate in a concentration of 0.2 mg / mL in the mobile phase solution ("STD-1" and "STD-2"). Standard solutions are stored in refrigeration when they are not in use, and fresh solutions are prepared daily. Sample solutions of trimetrexate anhydrous and trimetrexate monohydrate at 0.2 mg / mL are also prepared in the mobile phase solution. The system is reviewed before testing the sample solutions by analyzing the reproduction capacity of trimetrexate peak area measurements for six injections of the standard trimetrexate solution (STD-1), trimetrexate peak symmetry as well as correspondence between the standard preparations duplicates. The acceptance criteria are the following: Reproducibility: < 2.0% RSD Symmetry: < 2.0 (queue factor) Standard correspondence: < 2% Average peak areas of < 2.0 to calculate the standard areas corrected in accordance with what is described below. For test data, the HPLC operating parameters are as follows: Flow rate: 1.5 mL / minute Wavelength of 235 nm detection: Injection volume: 10 μL Column temperature: Ambient temperature (15-30 ° C) Experiment time: 12 minutes (1 minute after the typical trimetrexate integration peak: Attenuation 32 for the first 8 minutes, then 512 Each sample solution is tested, and the purity is calculated For the determination of impurities, the operating parameters they are, as before, except that the experiment time is extended to 30 minutes to detect all possible impurities and / or all degradation products, and an attenuation of 32 is employed. A mobile phase target is first tested, followed by A sample solution The calculations are made as follows: CSTD = (mg STD x purity STD (as decimal)) -s- 100 L Corrected standard area = standard peak area H- CSTD Standard area corrected p romedio = (corrected standard area (STD-1) + corrected standard area (STD-2)) - * • 2 mg found = (sample area average area corrected standard) x dilution mL Purity (% weight / weight) = [(mg found x 100%) + mg of sample weighted)] x [100 -s- (100-M)] Where M is the percentage humidity. For the impurity calculations, the peaks not present in the white chromatogram (and not the frontal perturbations of the solvent) are identified, and the following calculations are made: Relative retention time (RRT) = r? Mp / rTMtx Peak areas ( %) = [peak area (imp) -i- (S peak area (all impurities + TMTX))] x 100. Results Samples of the anhydrous and monohydrate compounds were initially tested to determine purity and moisture content. The samples were stored for 4 weeks either at 25 ° C or at 50 ° C. HPLC chromatograms were recorded for samples stored at each temperature after 3 days, 1 week, 2 weeks and 4 weeks of storage, and samples they were tested in each time interval PATRA to determine the purity, content of impurities and water. Figure 7 shows the HPLC chromatograms for samples stored at 50 ° C for 4 weeks. In Figure 7, trace A shows the chromatogram for the anhydrous sample, trace B shows trimetrexate monohydrate and C is a solvent blank. The peak at approximately 13 minutes corresponds to the non-degraded compound; This peak is truncated in the figure in order to expand the Y axis to see the impurities. Figure 7 shows the impurities in the anhydrous sample in the region of 2 to 7 minutes and a large impurity at about 20 minutes. In contrast to the anhydrous sample, trimetrexate monohydrate showed no significant degradation products after 4 weeks at a temperature of 50 ° C. Table 9 summarizes the stability data. Table 9: Thermal stability of TMH Sample Time Trial Amine (weight / weight) (percentage area Monohydrate Initial 99.6 0.1 A 25 ° C 3 days 101.4 0.1 1 week 96.3 0.1 2 weeks 99.4 0.1 4 weeks 99.6 0.1 A 50 ° C 3 days 99.4 0.1 1 week 98.6 0.1 2 weeks 98.7 0.1 4 weeks 99.6 0.2 Initial Anhydrous 98.5 0.2 A 25 ° C 3 days 100.4 0.2 1 week 96.6 0.3 2 weeks 98.4 0.4 4 weeks 97.6 0.8 A 50 ° C 3 days 99.5 0.4 1 week 95.0 0.7 2 weeks 95.8 1.4 4 weeks 92.7 2.9 Sample Time Total impurities Percentage (percentage area) of moisture Monohydrate Initial 0.2 4.9 At 25 ° C 3 days 0.2 4.7 • 1 week 0.1 4.5 2 weeks 0.1 4.9 4 weeks 0.3 4.3 At 50 ° C 3 days 0.3 4.7 1 week 0.2 4.6 2 weeks 0.1 4.8 • 10 4 4 sseemmaannaass 0 0..33 4.4 Initial Anhydrous 0.3 0.1 At 25 ° C 3 days 0.4 0.3 1 week 0.4 0.4 2 weeks 0.5 0.2 15 4 4 sseemmaannaass 1 1..00 < 0.1 A 50 ° C 3 days 0.7 0.4 1 week 1.2 0.7 • 2 weeks 2.1 0.3 4 weeks 4.5 < 0.1 20 The "amine" entry in Table 9 corresponds to the amine degradation product which is prominent in Figure 7 as the large peak at about 20 minutes in the anhydrous sample. This degradation product was isolated and identified as 6-aminomethyl-5-methyl-2,4-quinazolindiamine. 25 It is a pale yellow powder with a molecular formula of C 10 H 13 N 5 and a formula weight of 203.25 g / mol. the structure of the compound is presented below The ultraviolet ray absorption spectrum of the degradation product was measured using an IBM 9420 UV / VIS spectrophotometer. A solution of 0.005 g / L of the compound in ethanol was prepared, and the spectrum was measured using 1.0 cm cells. The molar absorption capacities of the three main absorption maxima are shown in Table 10. Table 10: Absorption maxima and absorption capacities of anhydrous trimetrexate degradation product? (nm) molar absorption capacity (e) 240 3.7208 x 104 274 8.371 x 103 343 3.720 x 103 6.7. EXAMPLE 7: PREPARATION OF TRIMETREXATE MONOHYDRATE FROM TRIMETREXATE ACETATE HYDRATE Trimetrexate monohydrate was produced from trimetrexate acetate hydrate, in accordance with the method of Scheme 1. 6.7.1. Materials the materials used and their source, or a representative source, appear in table 11. At each step of the synthesis, the reagent container (a steel reactor) is cleaned, dried and purged with nitrogen first. Table 11: Materials in the synthesis of TMH Raw materials Chemical name Form used Supplier (or equivalent) Trimetrixture Acetate, Crystalline Raw Bioscience (Parke-Davis) Reagents Ammonia solution to Staub, Jákle 25% Gluconic acid solution to Fluka 35-55% Wacial liquid glacial acetic acid Wacker Crystalline sodium chloride Jákle Reagents with catalytic amount entry Metabolite Jákle crystalline sodium Solvents n-butanol liquid Biesterfeld Water deionized liquid Liquid ethanol Jakle, Staub • Jákle liquid dimethylformamide (Biesterfeld) Auxiliary agents Tonsil (= bentonite) Sud-Chemie powder Hyflo Supercel powder Jákle Activated carbon powder Jákle, Biesterfeld • 10 Intermediates Trimetrexate Base, Crude Crystalline Trimetrexate Crystalline Base Additive DMF, pure 15 Trimetrexate Crystalline Hydrochloride Final Product • Sieve / Mix Monohydrate • Trimetrexate 20 6.7.2. STEP 1: TRIMETREXATE BASE, CRUDE The reactor is charged with 41.5 L of n-butanol and 10.4 L of deionized water. 6.3 kg of crude trimetrexate acetate is then added. Then add 3 g of sodium metabisulfite, 0.65 L of ammonia, 1 kg of Tonsil and 1 Kg of Supercel.

The reaction mixture is heated to a temperature of 90 ° C until reaching a gentle reflux, and said mixture is • stirred for 10 minutes. Then, a pressure filtration is carried out with a preheated filter tube at approximately 1 bar, in PE cylinders. The tube is then rinsed with a mixture of 4 L of n-butanol and 1 L of deionized water. The filtrate is transferred into the cleaned reactor (cleaned by rinsing with 5 liters of a 4: 1 mixture of n-butanol / water deionized) and heated to a temperature of 70 ° C. Then 1.95 L of ammonia are added. The base crystallizes after about 5 minutes. The reaction mixture is cooled to a temperature of 20 ° C and filtered using vacuum. The filter cake is washed with 5 L of water deionized and 5 L of ethanol (80%, using 4 parts by volume of ethanol and one part by volume of water). The yield is approximately 5.6 kg of wet substance, or 4.4 + 0.5 kg of dry product (calculated), which corresponds to a yield of 84 ± 10% in relation to the crude trimetrexate acetate. 6.7.3. STEP 2: TRIMETREXATE BASE ADDUCT, DMF the reaction vessel is loaded with 10.4 L of dimethylformamide (DMF) and 1.04 L of deionized water, then 4.35 kg of the trimetrexate (dried) base is added.

Step 1. The solution is heated to 100 ° C, then cooled to 75 ° C, and 5.2 L of ethanol are added. The solution is further cooled to 55-60 ° C and maintained until crystallization occurs. After crystallization, the solution is cooled to 10 ° C and filtered using vacuum. The crystals are washed twice with 2.6 L of ethanol (80% volume / volume). Alternatively, the same procedure can be used with 4.7 kg (with reference to the dried substance) of the wet trimetrexate base yield of step 1. The yield is 3.9 ± 0.5 kg of wet product or 3.0 ± 0.3 kg of dried substance ( calculated), which corresponds to a yield of 69 ± 7% in relation to the initial raw material of trimetrexate. 6.7.4. STEP 3: TRIMETREXATE HYDROCHLORIDE 2.85 kg of trimetrexate adduct DMF from step 2 (known as dried material) is suspended in 45 L of warm deionized water and heated to 50 ° C. 3.9 kg of gluconic acid (aqueous solution) is added. 35-55, weight with reference to 50% content), resulting in a dark, cloudy solution. 0.05 kg of activated carbon and 0.1 kg of Supercel are added, and the mixture is stirred for 10 minutes at a temperature of 50 ° C. The mixture is then filtered under pressure at 0.5 bar in PE cylinders and the filter duct is rinsed with 5 L of lukewarm deionized water. The reaction vessel is thoroughly washed with lukewarm water, and the filtrate is recycled to the vessel. 0.167 L of glacial acetic acid is added at 50 ° C, followed by a solution of 0.583 kg of sodium chloride in 2.5 L of deionized water. During this operation, the product is crystallizing. The suspension is stirred for 10 minutes at a temperature of 45-50 ° C and then cooled to 20 ° C. It is then filtered and washed with 5 L of deionized water and 5 L of ethanol (80% w / w). The yield of wet substance is 4.0 ± 0.5 kg, or 2.6 ± 0.3 kg of dried substance, which corresponds to a yield of 87 ± 10% in relation to the initial material of the trimetrexate DMF base adduct. 6.7.5. STEP 4: TRIMETREXATE MONOHYDRATE 2.86 kg of trimetrexate hydrochloride from step 3 is suspended in 30 L of deionized water and 10 L of n-butanol. The mixture is heated to 80 ° C and, without additional heating, 0.833 L of ammonia (25%) is added. The hydrochloride dissolves initially, but after about 2 minutes the base is precipitated. The mixture is stirred at a temperature of 70-80 ° C for 10 minutes and then cooled to a temperature of 10 ° C, followed by filtration using vacuum. The filtrate is washed with 5 L of deionized water and 5 L of ethanol (80% volume / volume) the wet material is dried under vacuum at 20-30 mbar for 15-20 hours at a temperature of 60 ° C in a dryer of vacuum tray, or preferably at a temperature of 50 ° C for about 4-8 hours in a rotary vacuum dryer. Immediately after drying, the product is sieved • with a 0.5 mm mesh with a maximum rotor speed. The batch-type unit container (fiber drum) with 5 PE insert (bag that can be folded) is connected directly to the exit funnel of the screening machine through a tension band. From the operating platform the dried product is supplied in portions to the feeding space of the screening machine. • 10 Immediately after sieving, the product is transferred to the mixer, and the material is mixed for 30 minutes. The yield of wet substance is 2.9 ± 0.5 kg, or 2.4 ± 0.2 kg of sifted substance, which corresponds to a yield of 92 ± 8% in relation to the initial material of trimetrexate hychlorochloride. 6.8. EXAMPLE 8: PREPARATION OF TRIMETREXATE MONOHYDRATE A • STARTING FROM QUINAZOLINE ALDEHYDE FORMAT Trimetrexate monohydrate can be produced from quinazoline aldehyde format or diformate, according to the method of, Scheme 2. The following is a process for the production of a typical lot (3.5 kg) of trimetrexate monohydrate, using the initial material diformate. 6.8.1. MATERIALS 25 All materials are easily available from several commercial suppliers. The initial material, format or quinazoline aldehyde diformate can be synthesized by reduction of the corresponding nitrile, 2,4-diamino-5-methyl-6-quinazoline carbonitrile, with Raney nickel and formic acid (see Biochem. Pharmacology, 33, 3251 (1984)). At each step of the synthesis, the reagent vessel (a steel reactor) is first cleaned, dried and purged with nitrogen. 6.8.2. STEP 1: QUINAZOLINE ALDEHYDE BASE • 10 The reaction vessel (a 400 L enameled stainless steel reactor) is charged with a mixture of 13.5 L of n-butanol and 9 L of water. To this is added 5.4 kg of quinazoline aldehyde diformate. After the addition of 90 g of EDTA, the mixture is heated to a temperature of 80 ° C. At this temperature, 0.9 L of TEA and 2.25 L of ammonia are added, raising the pH to more than 8.5. The mixture is heated to 90 ° C (gentle reflux) and stirred to this • temperature for 20 minutes. Afterwards, the suspension is cooled to a temperature of 20-25 ° C and filtered by suction. The filtered portions are washed with at least 1.8 L of n-butanol, 1.8 L of ethanol and 1.8 L of water. A sample is taken for control test according to appearance (wet olive-yellow to brown powder) and NMR spectrum. 25 A typical yield is 3.6 to 3.9 kg (dry basis), which corresponds to 89 to 97% relative to the initial material of quinazoline aldehyde diformate. 6.8.3. STEP 2: QUINAZOLINE SCHIFF BASE The reaction vessel (400 L enameled steel reactor) is charged with 22 L of n-butanol and 4.4 L of toluene. 3.87 kg of base of wet quinazoline aldehyde (from step 1, known as dry weight) and 3.38 kg of 3,4,5-trimethoxyaniline are added and the mixture is dehydrated by azeotropic distillation from 89 ° C to 110 ° C as liquid phase temperature, providing approximately 0.64 L of aqueous phase. The amount of water generated is used as a control to monitor the progress of the reaction. The mixture is then cooled to a temperature of 20-25 ° C and the Schiff base is removed by suction filtration. The filtered portions are washed with at least 3.5 L of n-butanol and 2.5 L of t-butyl methyl ether. A sample is taken for control test in accordance with the appearance (plates yellowish to brown) and NMR spectrum, and the Schiff base is taken directly to the next step to minimize contact with moisture due to the hydrolytic nature of the Schiff base. (See section 5.4, above). A typical yield is 5.3 to 6.4 kg (dry basis), which corresponds to 82 to 89% in relation to the initial base material of quinazoline aldehyde. 6.8.4. STEP 3: TRIMETREXATE ACETATE The reaction vessel (400 L enameled steel reactor) is charged with 30 L of tetrahydrofuran (THF), 7.3 L of water, 270 g of sodium carbonate, 5.85 kg of Schiff's base. quinazoline (from step 2, known as dry weight) and 165 g 5 from 3, 4, 5-trimethoxyaniline. The mixture is heated to a temperature of about 45 ° C. A solution of 0.55 kg of sodium borohydride dissolved in 2.7 L of water and 5 mL of sodium hydroxide is slowly added over a period of 3 to 5 hours to the reactor, during that time the reactor is • 10 purged with nitrogen. After finishing the addition of sodium borohydride solution, the reaction is stirred for 10 minutes at a temperature of 63-65 ° C. The progress of the reaction is monitored by TLC. If the amount of initial material is greater than 0.5%, an amount is added Additional sodium borohydride (calculated on a molar basis) is added to the reflux reaction. Approximately 27 L of THF is removed by distillation under normal pressure at a temperature of 65-68 ° C. 10 L of n-butanol and 5 L of water are added. They are removed by distillation about 5 L of a THF / butanol / water mixture until the temperature of the reaction mixture reaches 85 ° C. The reaction is then cooled to 5-10 ° C and the two phase mixture is filtered under vacuum. Each filtered portion is washed with at least 10 L of water. The base of humid trimetrexate crude (5.65 kg) is suspended in a mixture of 32 L of ethanol and 9 L of water. This suspension is heated to a temperature of 70 ° C and 0.76 L of lactic acid and 0.685 L of acetic acid are added. The resulting solution is mixed with 0.35 kg of Tonsil and 0.1 kg of activated carbon and the solution is filtered with pressure at 0.5 bar at a temperature of 70 ° C. To the filtrate is added 0.59 kg of sodium acetate in 2.3 L of water and 1 L of glacial acetic acid. The mixture is stirred for 30 minutes at a temperature of 70-75 ° C. After cooling to 20 ° C, the suspension obtained is filtered in • 10 empty. Each filtered portion is washed with at least 4.5 L of acetic acid. A sample is taken for control test according to appearance (yellow-green solid, wet), HPLC retention time and HPLC assay (NLT 98% w / w on an anhydrous base). 15 A typical yield is 5.5 to 6.5 kg (dry basis), which corresponds to 77 to 91% in relation to the initial Schiff base material of quinazoline. • 6.8.5. STEP 4: TRIMETREXATE MONOHYDRATE The reaction vessel (400 steel enameled reactor) L) is charged with 47 L of n-butanol and 8 L of water. 6 kg of trimetrexate acetate (from step 3, relative to dry weight), 140 g of ascorbic acid and 0.54 L of ammonia are added. The mixture is heated to a temperature of 90 ° C and stirred for 30 minutes until all the material is dissolved. 0.3 kg of Tonsil is added to the reaction mixture and the reaction is stirred for 10 minutes at a temperature of 90 ° C before being filtered under pressure at a temperature of 80 ° C to 0.5 bar. The filtrate is mixed with 0.67 L of sodium hydroxide and 1.48 L of ammonia at a temperature of about 80 ° C. The mixture is cooled to 15-20 ° C and stirred at this temperature for 30 minutes. The suspension obtained is filtered in vacuum. Each filtered portion is washed with at least 4 L of water and 2.7 L of 2-propanol. The reaction vessel is purged with nitrogen and the trace level amounts of 2-propanol in the product are removed using the following procedure. 2-methoxypropanol (31 L) and the wet trimetrexate base are fed to the reactor. The mixture is heated to a temperature of 110-115 ° C to remove traces of 2-propanol, and then allowed to cool to 105 ° C. Tonsil (0.5 kg) is added to the mixture. The reaction is heated again to 110-115 ° C and filtered with pressure at 0.5 bar and 110 ° C. The filtrate is cooled to 15-20 ° C to effect crystallization. After stirring for 20 minutes at 20 ° C, the product is removed by vacuum filtration. The filtered portion is washed with at least 4 L of 2-propanol. The conversion of the adduct of 2-methoxypropanol to the free base is carried out in the following manner. The reactor is charged with 27 L of ethanol, 4.9 L of water and the adduct of 2-methoxypropanol. The mixture is then heated to a temperature of 78-80 ° C under reflux, and stirred at this temperature for 30 minutes. After cooling to a temperature of 15-20 ° C to effect crystallization, the product is filtered in vacuum. Each filtered portion is washed with at least 4 L of water. The wet product is dried at a temperature of 70 ° C and 20-30 mbar for 15-20 hours in a tray dryer in vacuum, or preferably at a temperature of 50 ° C and under a pressure of 20-30 mbar for about 4-8 hours in a rotary vacuum dryer. The dried trimetrexate monohydrate base is sieved (500μ) and mixed. A representative sample is removed for testing purposes. A typical yield is 4.1 to 5.0 kg (dry basis), which corresponds to 79 to 96% in relation to the initial material of trimetrexate acetate. If any of the steps of the synthesis does not produce material that complies with the control test specification, the material may be subjected to further recrystallization in accordance with the same procedures described herein for each step. If the water or solvent content in step 4 is out of specification, drying, sieving and mixing can be repeated. 6. 9. EXAMPLE BASIC CHARACTERIZATION OF SCHIFF DE QUINAZOLINE The structure and identity of the Schiff base of quinazoline, 2, 4-diamino-5-methyl-6- [(3,4,5-trimethoxyphenylimino) -methynyl] -quinazoline, were confirmed using various analytical methods. Ultraviolet Absorption The ultraviolet absorption spectrum of the quinazoline Schiff base was measured using a lambda 2 UV spectrophotometer from Perkin-Elmer. A solution of 0.005 g / L of Schiff base of quinazoline in methanol was prepared, and the spectrum was obtained using 1.0 cm cells. The molar absorption capacities of the compound in the three main absorption maxima observed are shown in Table 12. Table 12: Absorption maxima and absorption capacities of Schiff base of quinazoline? (nm) molar absorption capacity (e) 205 3.9497 x 10b 247 2.9929 x 105 352 2.7137 x 105 Infrared Absorption The infrared spectrum was recorded using a model 740 infrared spectrophotometer from Nicolet. A potassium bromide nodule was prepared in a concentration of approximately 0.5% (w / w). The main spectral characteristics and their assignments appear in Table 13. Table 13: Schiff's base infrared spectrum of • Quinazoline No. wave (cm "1) assignment 3550-3300 segment -NH2 3146, 3114 segment CH aromatic 2996-2800 segment CH3 1662 segment -C = NW 10 1617 deformation -NH2 1607-1400 segment C = C, C = N aromatic 1228 segment = C-0 of aryl ether 1128 def in plane aromatic CH 897 out of plane CH 15 aromatic proton NMR and 13C The proton NMR spectrum (1H) for the compound was measured at 300.136 MHz using a NMR Bruker AMX300 spectrometer A spectral width was measured at 4504.5 Hz using 32K points data with a signal averaging 16 scans. The sample was prepared by dissolving 37 mg in 1.0 mL of dimethylsulfoxide-dß / to which TMS had been added as reference. The spectrum data are shown in Table 14. Table 14: 1 H NMR spectrum of quinazoline Schiff base d (ppm) multiplicity no. of protons 8.88 s 1 8.14 d, J = 8.9 Hz 1 7.10 d, J = 8.9 Hz • 1 6.96 bs 2 6.60 s 2 6.25 bs 2 3.83 s 6 3.67 s 3 2.92 s 3 • 10 An experiment of difference of NOE was made to determine the configuration around the imine double bond and to verify the chemical change assignment of the C7 proton of the quinazoline ring. With this experiment, a selected resonance 15 was irradiated during the pulse delay. Protons that are within 5 to 7 angstroms of the irradiated proton show an improvement in their signal. These protons have an increased signal • are identified by subtracting a normal spectrum from the enhanced spectrum. 20 The imine proton was irradiated for the NOE difference experiment and a strong increase in protons 2 was observed? 6 'in the trimethoxyaniline ring and the 5-methyl protons of the quinazoline moiety. This improvement shows that the expected trans configuration exists around 25 of the imine double bond since a cis configuration could not provide an increase of NOE to the protons 2 ', 6'. A weaker increase was observed in the resonance a • 8.14 ppm, which identifies it as proton 7 in the quinazoline ring. 5 A 13 C NMR spectrum was also recorded, and was consistent with the Schiff base structure of quinazoline. Mass spectroscopy The mass spectrum of the compound was obtained using direct input electron impact ionization. He spectrum was measured with a HP 5989A MS Engine mass spectrometer with a hyperbolic quadrupole mass filter. The probe was programmed from 35 ° C to 250 ° C with an increase of 25 ° C / min. The ionization energy was 70 eV. The mass spectrum appears in table 15. 15 Table 15: Mass spectrometry data m / z relative abundance (%) identity 367 100 M + 350 84 M + - NH3 335 34 M + - CH30H 20 200 32 M + - trimethoxyphenyl 185 70 M + - TMA 168 30 [trimethoxybenzene] + TMA = portion 3, 4, 5-trimethoxyaniline trimetrexate Water content The water content in the sample was measured through the Karl Fisher titration. It was found that the sample contained 1.0% water (0.21 mol). Melting points The fusion range was measured by means of calorimetry by differential scan, using a Shimadzu DSC-50 instrument. The melting range was 245.4 to 247.5 ° C. Elemental analysis The compound for C, H, N content was analyzed using a CEC Model 240-XA CHN analyzer. The results appear at • 10 in Table 16. Table 16: elemental analysis of C, H and N Element% theoretical% measured carbon 61.51% 61.81 hydrogen 5.81 6.03 15 nitrogen 18.86 19.39 The invention described and claimed herein is not limited to as to its scope to the specific modalities disclosed herein since these modalities are merely illustrations of various aspects of the invention. Any The equivalent mode is within the scope of this invention. In fact, various modifications to the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also within of the scope of the appended claims.

All references mentioned in the present application are incorporated by reference in their entirety.

Claims

CLAIMS 2, 4-diamino-5-methyl-1-6 - [(3,4,5-trimethoxyanilino) ethyl] quinazoline thermally stable, wherein said compound is not a salt.
2. The thermally stable 2,4-diamino-5-methyl-6- [(3,4,5-trimethoxyanilino) methyl] quinazoline of claim 1, wherein said compound is a hydrate. 2, 4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyanilino) methyl] quinazoline monohydrate. Crystalline 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyanilino) methyl] quinazoline monohydrate. The crystalline 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyanilino) ethyl] quinazoline monohydrate according to claim 4 having a powder diffraction pattern by x-ray essentially equal to Figure 1. Crystalline 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyanilino) methyl] quinazoline monohydrate according to claim 4 having a powder diffraction pattern by X-rays essentially equal to Table 1. A crystalline monohydrate of 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyanilino) methyl] quinazoline which belongs to the space group Pl (# 2) and which has a cell triclinic with dimensions of a = 7.699 A, b = 9.606 A and c = 13.012 A. 8. A thermally stable compound of claim 1, 2 or 3, wherein said compound is sterile. • 9. A crystalline monohydrate of 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyanilino) methyl] quinazoline of the 5 claim 4, 5, 6 or 7, wherein said compound is sterile. 10. A method for the production of 2,4-diamino-5-methyl-6- [(3,4,5-tri-ethoxyanilino) ethyl] quinazoline monohydrate comprising: • 10 a. the preparation of a crude trimetrexate base from trimetrexate acetate hydrate; b. recrystallization of the crude trimetrexate base with dimethylformamide (DMF) to produce a pure trimetrexate-DMF adduct; 15 c. converting trimetrexate-DMF adduct to trimetrexate hydrochloride; and d. convert trimetrexate hydrochloride into • Pure crystalline trimetrexate monohydrate. 11. The method according to claim 10 in which step (a) is carried out in water, aliphatic C2 to C4 alcohols or a mixture thereof. 12. The method according to claim 11 wherein the solvent is a mixture of "n-butanol and water 13. The method according to claim 12 wherein n-butanol and water are in a proportion from 1: 1 to 10: 1 14. The method according to claim 10 wherein step (a) comprises preparing a solution of trimetrexate acetate in a base mixture of n-butanol and water; of a catalytic amount of sodium metabisulfite, filter the solution, further heat the solution to a temperature of about 50 to 90 ° C, and add aqueous ammonia to crystallize the crude base of trimetrexate 15. The method according to claim 14 wherein the filtration is carried out at a pressure of about 1 bar 16. The method according to claim 14 further comprising cooling the solution to room temperature after the crude trimetrexate crude base, crude trimetrexate base filtration and crude trimetrexate base wash. 17. The method according to claim 16 wherein the raw trimetrexate base is washed with ethanol, water or a mixture thereof. 18. The method according to claim 10 wherein step (b) comprises dissolving the crude base of trimetrexate in a solvent comprising dimethylformamide; heating the DMF solution; the addition of a C2 to C4 alcohol; and cooling the DMF solution to a temperature at which the trimetrexate DMF adduct crystallizes. 5 19, The method according to claim 18 further comprising filtering the trimetrexate-DMF adduct. 20, The method according to claim 19 further comprising washing the filtered adduct from • 10 trimetrexate-DMF with a C2 to C4 alcohol. 21, The method according to claim 10 wherein in step (c), the trimetrexate-DMF adduct is converted to trimetrexate hydrochloride via an intermediate product of trimetrexate gluconate. The method according to claim 21 wherein said trimetrexate gluconate intermediate product is produced by contacting • of the trimetrexate-DMF adduct with a gluconate source. 23. The method according to claim 21 wherein the intermediate of trimetrexate gluconate is converted to trimetrexate hydrochloride using acetic acid and an aqueous solution of sodium chloride to crystallize the 25 trimetrexate hydrochloride. The method according to claim 23 further comprising heating the trimetrexate gluconate solution. The method according to claim 23 further comprising the filtration of trimetrexate hydrochloride. The method according to claim 25 further comprising washing the filtered trimetrexate hydrochloride with water, a C2 to C alcohol, or a mixture thereof. The method according to claim 10 wherein step (d) comprises heating the trimetrexate hydrochloride in a mixture of water and a C2 to C4 alcohol and raising the pH of the suspension to precipitate the trimetrexate monohydrate. The method according to claim 27 further comprising filtering, washing, vacuum drying the trimetrexate monohydrate. The method according to claim 10 further comprising screening and optionally mixing the trimetrexate monohydrate. A method for the production of 2,4-diamino-5-methyl-6- [(3,4,5-trimethoxyanilino) methyl] quinazoline monohydrate comprising: a. the conversion of quinazoline aldehyde or quinazoline aldehyde diformate to carboxaldehyde hydrate of 2,4-diamino-5-methyl-6-quinazoline; jfl b. coupling the carboxaldehyde hydrate of 2,4-diamino-5-methyl-6-quinazoline with trimethoxyaniline 5 to produce 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyphenylimino) methyl] quinazoline; c. the reduction of 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyphenylimino) methyl] quinazoline in trimetrexate acetate hydrate; and • 10 d. the preparation of pure trimetrexate monohydrate by treatment of trimetrexate acetate hydrate with ammonia and purification of the trimetrexate monohydrate product. The method according to claim 30 in which step (a) comprises: heating a quinazoline aldehyde formatting solution or quinazoline aldehyde diformate in the presence of EDTA, triethylamine and a sufficient amount of ammonia to provide the solution 20 with a basic pH, at a reflux temperature and for a time sufficient to crystallize the carboxaldehyde hydrate of 2,4-diamino-5-methyl-6-quinazoline. 32. The method according to claim 31 wherein the solution of quinazoline aldehyde format or 25 quinazoline aldehyde diformate is prepared in a polar aqueous solvent. 33. The method according to claim 32 wherein the polar aqueous solvent is water, a C2-C4 alcohol or a mixture thereof. 34. The method according to claim 33 wherein the solvent is a mixture of n-butanol and water. 35. The method according to claim 34 wherein the solvent is a mixture of n-butanol and water in a ratio of 0.5: 1 to 3: 1. • 36. The method according to claim 31 wherein the basic pH is from about 8.0 to about 10.0, the reflux temperature is from about 70 ° C to about 100 ° C, and the time is from about 5 to 60. minutes 37. The method according to claim 31 further comprising filtering the carboxaldehyde hydrate of 2,4-diamino-5-methyl-6-quinazoline. 38. The method according to claim 33 further comprising washing the carboxaldehyde hydrate 20 of 2, 4-diamino-5-methyl-6-quinazoline with at least a portion of a C2 to C alcohol and at least a portion of water. 39. The method according to claim 30 wherein step (b) comprises: heating the hydrate 25 carboxaldehyde of 2,4-diamino-5-methyl-6-quinazoline in 7 a mixture of butanol and toluene to an azeotropic point; and distilling off the water of hydration to leave a phase containing 2,4-diamino-5-methyl-6- [(3,4,5-trimethoxyphenylimino) methyl] quinazoline. 40. The method according to claim 39 further comprising the filtration of 2,4-diamino-5-methyl-6- [(3, 4, 5-trimethoxyphenylimino) methyl] quinazoline. 41. The method according to claim 40 further comprising washing the 2, 4-diamino-5-methyl-6- (10- [(3,4,5-trimethoxyphenylimino) methyl] quinazoline filtered with butanol and an ether . 42. The method according to claim 30 wherein step (c) comprises heating 2,4-diamino-5-methyl-6- [(3,4,5-trimethoxyphenylimino) methyl] quinazoline in a mixing tetrahydrofuran and water in the presence of a reducing agent to produce a crude trimetrexate base, and converting the crude base of trimetrexate to trimetrexate acetate. 43. The method according to claim 42 wherein the reducing agent is sodium borohydride or an aqueous solution of sodium borohydride. 44. The method according to claim 43 wherein the aqueous sodium borohydride is added 25 gradually over a period of 1 to 10 hours. 45. The method according to claim 30 wherein step (c) is carried out in an inert gas jB selected from the group consisting of nitrogen, argon and helium. 46. The method according to claim 42 further comprising distilling off approximately 90% of the tetrahydrofuran; addition of alcohol and water; additional removal by distillation of tetrahydrofuran, alcohol and water; and cooling to produce a two-phase system containing the crude base of trimetrexate. 47. The method according to claim 42 wherein the step of converting the crude base of trimetrexate to trimetrexate acetate comprises: 15 the crude base of trimetrexate in a polar solvent or mixture of solvents; the addition of lactic acid, acetic acid, Tonsil and a catalytic amount of activated carbon, filtration to provide a filtrate; heating the filtrate in the presence of acetate 20 sodium and acetic acid; cooling of the filtrate; and vacuum filtration to obtain trimetrexate acetate. 48. The method according to claim 47 further comprising washing the trimetrexate acetate with acetic acid. 49. The method according to claim 30 wherein in step (d) the trimetrexate acetate is converted to trimetrexate monohydrate through an adduct of 2-methoxypropanol. 50. The method according to claim 49 wherein the adduct of 2-methoxypropanol is produced by: heating trimetrexate acetate with ascorbic acid and ammonia in an aqueous alcohol; the filtration to provide a filtrate; raising the pH and cooling the filtrate to obtain a trimetrexate adduct suspension of 2-methoxypropanol; and filtering and washing the adduct with at least a portion of water and at least a portion of 2-propanol. 51. The method according to claim 50 wherein said adduct is washed. 52. The method according to claim 50 wherein said aqueous alcohol is butanol-water. 53. The method according to claim 50, wherein the filtering step is carried out under pressure. 54. The method according to claim 50 further comprising purifying the adduct of methoxypropanol. 55. The method according to claim 49 wherein the adduct of 2-methoxypropanol is converted to trimetrexate monohydrate by: preparing a solution of the 2-methoxypropanol adduct with a solvent comprising a mixture of an alcohol U to C4 and water; heating to a reflux temperature; and the • cooling to crystallize trimetrexate monohydrate. 56. The method according to claim 55 further comprising vacuum filtration and washing the trimetrexate monohydrate with water. 57. The method according to claim 55 further comprising drying the monohydrate of 10 trimetrexate in vacuum. 58. The method according to claim 57 wherein the drying is carried out at a pressure of about 1 to 50 mbar, at a temperature of about 40 to 80 ° C, and for a period of 15 approximately 2 to 40 hours. 59. The method according to claim 30 further comprising screening and mixing the trimetrexate monohydrate. 60. A compound having the formula: Or else pharmaceutically acceptable salts, solvates or hydrates thereof. A compound that has the formula: or pharmaceutically acceptable salts, solvates or hydrates thereof. A compound that has the formula: or 'pharmaceutically acceptable salts, solvates or hydrates thereof.