MXPA00003184A

MXPA00003184A - Processes and intermediates for preparing anti-cancer compounds

Info

Publication number: MXPA00003184A
Application number: MXPA/A/2000/003184A
Authority: MX
Inventors: Shelton Lehner Richard; Norris Timothy; Paul Santafianos Dinos
Original assignee: Pfizer Products Inc
Priority date: 1999-03-31
Filing date: 2000-03-30
Publication date: 2001-12-04

Abstract

The present invention relates to methods and intermediates for preparing compounds of the formula 1àààand the pharmaceutically acceptable salts and solvates thereof, as well as structurally related compounds, wherein R1, R2 and R15 are as defined herein. The foregoing compounds are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals. The present invention also relates to a method of preparing compounds of the formula 9àààand the pharmaceutically acceptable salts and solvates thereof, wherein R6-R10 and R15 are as defined herein.

Description

PROCEDURES AND INTERMEDIATES FOR PREPARING ANTICANCEROS COMPOUNDS DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION The present invention relates to methods and intermediates for preparing compounds that are useful in the treatment of hyperproliferative disorders, such as cancers in mammary cells. U.S. Patent 5,747,498 issued May 5, 1998 and which is incorporated herein by reference in its entirety, refers to a new series of quinazoline derivatives, including hydrochloride [6,7-]. bis (2-me-toxietoxy) quinazolin-4-yl] - (3-ethynylphenyl) amine, which are inhibitors of the erbB family of oncogenic and proto-oncogenic tyrosine kinase proteins, such as the epidermal growth factor receptor (EGFR), and which, therefore, are useful for the treatment of proliferative disorders, such as cancers, in man. The United States provisional patent application entitled "N- (3-ethynylphenylamino) -6,7-bis (2-methoxyethoxy) -4-quinazolinelamide anhydrous monohydrate mesylate", filed on April 29, 1998, on behalf of of inventors T. Norris, D. Santafianos, DJ . Alien, R.M. Shanker and J.W. Raggon, file of agent PC 10074, which is incorporated herein by reference in its entirety, refers to the anhydrous and hydrated forms of N- (3-ethynylphenylamino) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine mesylate having the same anticancer utility as the corresponding hydrochloride salt mentioned above. The present invention relates to methods and intermediates for preparing anticancer compounds cited in the patent and in the United States patent application cited above.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing compounds of formula 1 and pharmaceutically acceptable salts and solvates of said compounds, formula wherein: each of R 1 and R 2 is independently selected from C 1 -C 0 alkyl and C 1 -C 6 alkoxy) wherein said alkyl and alkoxy are optionally substituted with up to 2 substituents independently selected from hydroxy and Ci-C alco alkoxy and R15 is H, alkyl C.-Co or- (CH2) q (aryl C6-Co), wherein q is an integer from 0 to 4, process comprising treating a compound of formula 2 wherein R15, R1 and R2 are as defined above and G is a blocking group selected from -C (OH) R3R4 and -SR3R4R5 and each of R3, R4 and R5 is independently C-C6 alkyl , with (a) an alkali metal or alkaline earth metal hydroxide in a solvent comprising a C.sub.1 -C. or hydroxy-substituted alkyl, where G is -C (OH) R3R4, or (b) a tetra (alkyl) fluoride compound C.-Ca.ammonium in an aprotic solvent, when G is -SiR3R4R5 In a preferred embodiment, when G is -C (OH) R3R4, said solvent is a secondary alcohol, such as butan-2-ol- or isopropanol, and the said alkali metal or alkaline earth metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, preferably sodium hydroxide, In another preferred embodiment, when G is -SiR3R4R5, the cited tetra fluoride compound (alkyl C.-Cßjamonio is tetra (n-butyl) ammonium fluoride and said aprotic solvent is selected from tetrahydrofuran (TFH), diethyl ester, dimethoxyethane (DME), toluene, dichloromethane, chloroform and mixtures of two or more of the aforementioned solvents, most preferably THF. The present invention also relates to the preparation of a compound of formula 2, described above, which process comprises treating a compound of formula 3 wherein R1 and R2 are as defined above, with a compound of formula 4 wherein G and R15 are as defined for the said compound of formula 2. In a preferred embodiment of the above process, the compound of formula 3 is treated with the compound of formula 4 in an organic solvent, such as dimethylformamide (DMF) dimethylsulfoxide (DMSO), THF, acetonitrile (MeCN) or a mixture of two or more of the aforementioned solvents, preferably acetonitrile. The present invention also relates to the preparation of the compound of formula 3, defined above, which preparation comprises treating a compound of formula with thionyl chloride in anhydrous dichloromethane. In a preferred embodiment of each of the reactions described above, R1 and R2 are 2-methoxyethoxy and R15 is hydrogen. The present invention also relates to the preparation of compounds of formulas 6 and 7 and of the pharmaceutically acceptable salts and solvates thereof, formulas in which R15 is as defined above and R6 is alkyl C.-Co or -20 (CH2) mO (CH2) nCH3, R7 is alkyl C.-C .0 or - (alkyl C.-C6) (aryl Ce-Cι), in which the aforementioned R 7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (C.sub.6-alkyl) sulfonyl, C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.2 alkoxy, C.sub.6 -C.sub.30 aryloxy and (C.sub.6 -C.sub.0 alkylsulfonyl), each m is independently a whole number from 1 to 6 and n is an integer from 0 to 3, which preparation comprises treating a compound of formula 8 Wherein G 1 -C (OH) R 3 R 4 and R 15, R 6, R 3 and R 4 are as defined above, with a primary or secondary alcohol of the formula R 7 -OH, wherein R 7 is as defined above, in the presence of an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, hydroxide lithium, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, preferably sodium hydroxide. In a preferred embodiment of the above reaction, R6 is 2-methoxyethoxy and said alcohol of formula R7-OH is preferably a secondary alcohol. The present invention also relates to a process for preparing compounds of formula 9 Aff -aaati-diMMa -múii i AAA- A? and the pharmaceutically acceptable salts and solvates thereof, wherein R15, R6 and R7 are as defined above, each of R8, R9, and R10 is independently selected from H, C1-C10 alkyl, halo, cyano , nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR11, -C (O) R11 '-C (O) OR11, -NR12C (O) OR14, -OC (O) R11, -NR12SO2R14, -SO2NR11R12, -NR12C (O) R 11, -C (O) NR 11 R 12, -NR 11 R 12, -S (O) j (CH 2) q (for C 6 -C 0), -S (O) j (C 6 alkyl), wherein is an integer from 0 to 2, - (CH2) q (aryl Ce-Cío), -O (CH2) q (aryl Ce-Cío), -NR12 (CH2) q (aryl Ce-Cío), and - ( CH2) q (heterocyclic group of 4-10 members), where q is an integer from 0 to 4; optionally containing said alkyl group 1 or 2 heteroorrests selected from O, -S (O) r, wherein j is an integer from 0 to 2, and -N (R12) -, with the proviso that the O atoms , two S atoms or one O atom and one S atom are not directly bonded to each other; the aforementioned aryl and heterocyclic groups being optionally condensed with a C 6 -C 6 aryl group, a saturated Cs-Cβ cyclic group or a 4-10 membered heterocyclic group; and being optionally substituted __ ^ ______ E, Í? Wa »?« I »« g¡ ^ (j¿g m & g ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR12SO2R14, -SO2MR 1R12, -C (O) R11, -C (O) OR11, -OC (O) R11, -NR 12 C (O) R 14, -NR 12 C (O) R 11, -C (O) NR 11 R 12, -NR 11 R 12, -OR 11, C 1 -C 10 alkyl, - (CH 2) q (C 6 -C 6 aryl) and (CH 2) q (4-10 membered heterocyclic group), wherein q is an integer ranging from 0 to 4, each R 11 is independently selected from H, C 1 -C 10 alkyl, - (CH 2) q (C 6 -C 6 aryl) ) and - (CH2) q (heterocyclic group of 4-10 members), wherein q is an integer ranging from 0 to 4, including the aforementioned alkyl group 1 or 2 haterorrestos selected from O, -S (O) r, where j is an integer from 0 to 2, and -N (R12) -, with the proviso that two O atoms, two S atoms or one O atom and one S atom are not directly bonded together; being optionally condensed the said aryl and heterocyclic R11 groups with a C6-C10 aryl group, a saturated Cs-Cβ cyclic group or a 4-10 membered heterocyclic group; and the aforementioned R11 substituents being optionally substituted, except H, with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R12, -C (O) OR12, - OC (O) R12, -NR12C (O) R13, -C (O) NR12R13, -NR12R13, hydroxy, C-C6 alkyl and CrC6 alkoxy, each of R12 R13 is independently H or CrC6 alkyl and R14 is selected from the substituents indicated in the definition of R11, except that R14 is not H, process comprising treating a compound of formula 10 Sjjj ^^ sjf? Gj ßg ^^ gíí ^ wherein R15, R6, R8, R9 and R10 are as defined above, with a primary or secondary alcohol of formula R7-OH, wherein R7 is as defined above, preferably a primary alcohol, in the presence of an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, preferably sodium hydroxide. The above compounds of formulas I, 6, 7 and 9 are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals. The present invention also relates to the intermediates of formula 2 described above with reference to the preparation of the compounds of formula 1. As used herein, the term "halo" includes, unless otherwise indicated, fluoro , chlorine, bromine or iodine. Preferred groups are fluoro, chloro and bromo. As used herein, the term "alkyl" includes, unless otherwise indicated, monovalent saturated hydrocarbon radicals having straight, branched or cyclic moieties or - ^ a ^^ and ^^^ at,! ^^ ..,. ", ___._, __., __, .. jS? "& ^. AA ^ i - ^^. ^ ... ^^ fe-i ^. ^^^^^^ .. a combination of the aforementioned remains. It is understood that, when said alkyl group includes cyclic moieties, at least three carbon atoms are required in said alkyl group. As used herein, the term "aryl" includes, unless otherwise indicated, an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl. As used herein, the term "4-10 membered heterocyclic group" includes, unless otherwise indicated, aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, each selected from O, S and N in which the said heterocyclic groups have from 4 to 10 atoms in their ring system. The non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system but the aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzocondensate ring systems and ring systems substituted with one or more oxo moieties. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanil, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3 , 6-tetrahydropyridinyl, 2-pyrrolinyl, 3- f ñr? -imfti - ** * - ¡jte-ká üjüí ^ faith * '. w .sub.1, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl. , imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-aza-bicyclo [4.1.0] heptanil, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolium, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The aforementioned groups, derived from the compounds listed above, they can be joined by a C or joined by an N when possible. For example, a pyrrole derivative group can be pyrrol-1-yl (linked by N) or pyrrole-3-yl (linked by a C). As used herein, the phrase "pharmaceutically acceptable salt or salts" includes, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of the present invention. The compounds prepared according to the present invention which are basic in nature can form a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of said basic compounds are those that form non-toxic acid addition salts, that is, salts that contain * ** ** * - - ^^ - ^ ^ *? ^^ - ^^^ ?? ^ i ^^ iA ^ et ?? t pharmacologically acceptable anions, such as the salts hydrochloride, hydrobromide, iodhidrato, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate , methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [that is, 1,1 '-methylene-b] (2-hydroxy-3-naphthoate)] The compounds prepared according to the present invention which include a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.The compounds prepared according to the present invention which are acidic in nature can form basic salts, with various cations pharmacologically acceptable. salts 5 include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention. The compounds prepared according to the present invention have asymmetric centers and, therefore, exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds prepared according to the present invention and to mixtures thereof. The compounds of formula 1 can also exist as tautomers. This g jjj ^^^^^ jju $ invención invention refers to the use of all these tautomers and mixtures thereof. The present invention also includes isotopically-labeled compounds prepared according to the present invention, and pharmaceutically acceptable salts thereof, which are identical to those cited in formula 1, except for the fact that one or more atoms are replaced by a atom that has an atomic mass or mass number different from the atomic mass or mass number that is usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F and 36C1, respectively. Within the scope of this invention are compounds prepared according to the present invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms. Certain isotopically-labeled compounds of the present invention, for example, those in which radioactive isotopes are incorporated with 3 H and 14 C, are useful in drug assays and / or distribution in substrate tissues. For their ease of preparation and detectability tritiated isotopes, that is, 3H, and carbon 14, that is, 14C, are preferred. In addition, replacement with heavier isotopes, such as deuterium, that is, 2H, can give certain therapeutic advantages resulting from their greater metabolic stability, for example, a half-life in Increased live or reduced dosage requirements and, therefore, may be preferred in some circumstances. The isotopically-labeled compounds of the formula of this invention and the prodrugs thereof can generally be prepared by carrying out the procedures described in the schemes and / or following examples and preparations, substituting an isotopically non-labeled reagent for an easily available isotopically-labeled reagent.

DETAILED DESCRIPTION OF THE INVENTION SCHEME 1 ? * *? 6mi ~ ^^. Í j ^ ¡| Jg | g _______ i_g__¡ ____ i____________ * »& .. s« &amp ... ¿^ a ^ jfa ^ ..

SCHEME 2 SCHEME 3 The methods of the present invention can be described with reference to schemes 1 to 3 above. In the reactions described below, all reactions are carried out at atmospheric pressure and at room temperature (approximately 20-25 ° C), unless other conditions are specified. In addition, unless otherwise indicated, the substituents R1-R10, R15, G and G1 are as described above. In scheme 1, compounds of formula 1 can be prepared by first treating the starting compound 5, which can be prepared according to procedures familiar to those skilled in the art, with thionyl chloride in anhydrous dichloromethane, at the reflux temperature (about 38-42 ° C at atmospheric pressure), to obtain the compound of formula 3. The compound of formula 2 can be obtained by treating the compound of formula 3 with the compound of formula 4 in an organic solvent, such as DMF, DMSO, THF, MeCN or a mixture of two or more of the aforementioned solvents, preferably MeCN, at a temperature ranging from 50 ° C to the reflux temperature, preferably the temperature of Reflux. The aforementioned acronyms are as defined in the "Brief description of the invention" described above. The compound of formula 1 can be prepared by treating the compound of formula 2 with an alkali metal or alkaline earth metal hydroxyl in a solvent comprising C 1 -C 10 alkyl substituted by at least one hydroxyl group, when G is -C (OH) R 3 R 4 , or with a tetrahydric (C 1 -C) alkyl ammonium fluoride compound in an aprotic solvent, when G is -SiR 3 R 4 R 5. When G is -C (OH) R3R4, the solvent is preferably a secondary alcohol, such as butan-2-ol or isopropanol, the aforementioned alkali metal or alkaline earth metal hydroxide of sodium hydroxide, lithium hydroxide, cesium hydroxide may be selected. , calcium hydroxide, magnesium hydroxide and potassium hydroxide, preferably sodium hydroxide, and the reaction is preferably carried out at a temperature ranging from about 100 ° C to about 150 ° C. When G is -SiR3R4R5, the compound tetra (alkyl CrC6) ammonium fluoride is preferably tetra (n-butyl) ammonium fluoride, the aprotic solvent can be selected from THF, diethyl ether, DME, toluene, dichloromethane, chloroform and a mixture of two or more of the aforementioned solvents, preferably THF, and the reaction is preferably carried out at a temperature ranging from about room temperature to about 70 ° C. The anticancer compounds of formula 1 can be converted to pharmaceutically acceptable salts as will be described below. In scheme 2, anticancer compounds of formulas 6 and 7 can be prepared by treating the intermediate of formula 8 with a primary or secondary alcohol of formula R7-OH, wherein R7 is as defined above, in the presence of a hydroxide of alkali metal or alkaline earth metal, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, preferably sodium hydroxide, at a temperature ranging from about 100 ° C to about 150 ° C. The use of a secondary alcohol of formula R7-OH will minimize the conversion to the asymmetric analog of formula 7 while the use of a primary alcohol of formula R7-OH will increase the relative concentration of the asymmetric analogue of formula 7. Therefore, depending of the analogue that is preferred, a primary or secondary alcohol may be preferred. The compounds of formulas 6 and 7 can be separated by various methods, such as chromatography, which are familiar to those skilled in the art. The compounds of formulas 6 and 7 can be converted into pharmaceutically acceptable salts, as will be described below. s ^ S ^ i ^ M ^ 6. - ^ ". K «» ** ~~ ^. * ^. * ^. * * »***? ^ ^ M». * In scheme 3, compounds of formula 9 can be prepared by treating compounds of formula 0 with a primary or secondary alcohol of formula R7-OH as described above in relation to scheme 2. Since the objective of the reaction of scheme 3 is the preparation of the asymmetric analog, it is preferred to use a primary alcohol of formula R7-OH. The compounds of formula 9 can be converted into pharmaceutically acceptable salts, as will be described below. Certain compounds prepared according to the present invention, mentioned above, may have asymmetric carbon atoms. Compounds that have a mixture of isomers with respect to one or more centers will exist as mixtures of diastereomers, which can be separated into their individual diastereomers based on differences in their physicochemical properties by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. All of these isomers, including mixtures of diastereomers, are considered part of the invention. The compounds mentioned above that are basic in nature can form a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable to be administered to mammals, it is sometimes desirable in practice to initially isolate the compound of the present invention, from the reaction mixture, in pharmaceutically unacceptable salt form and then simply convert this last in the compound in free base form by treatment with an alkaline reagent and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. By careful evaporation of the solvent, the desired solid salt is easily obtained. Also, the desired acid salt can be precipitated in a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution. The compounds mentioned above that are acidic in nature can form basic salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable basic salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Said non-toxic basic salts include those derived from said pharmacologically acceptable cations, such as sodium, potassium, calcium, magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired alkali metal alkoxide or metal hydroxide and then evaporating the resulting solution to dryness, ¡¡? ^^^ ¡¡¡¡¡¡¡¡¡gg ^^^ g gg ^ ¡g ^? ¡¡¡Gjg __ preferably at reduced pressure. Alternatively, they can also be prepared by mixing solutions of the acidic compounds in lower alkanois and the desired alkali metal alkoxide or metal hydroxide and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of the reagents are preferably employed to ensure that the reaction is complete and that the maximum yields of the desired final products are obtained. The examples provided below further exemplify the methods and intermediates of the present invention, although it is understood that the scope of the present invention is not limited by the following examples.

EXAMPLE 1 Preparation of 3-f (trimethylsilyl-ethylnitrobenzene A mixture of 1-bromo-3-nitrobenzene (10.0 g, 49.45 mmole) and trimethylsilylacetylene (8.4 ml, 59.34 mmole) was treated with triethylamine (33 ml) to give a small amount of white precipitate. The resulting mixture was treated with dichlorobis (triphenylphosphono) palladium II (7 mg, 0.01 mmol) and copper iodide (I) (8.5 mg, 0.04 mmol) and heated to 80-85 ° C (temperature of an oil bath). During 4 hours. The resulting bright yellow mixture was allowed to cool to room temperature and the solid was filtered off with the aid of triethylamine (33 ml). The transparent yellow solution ^^^ || The mixture was concentrated by evaporation and dried under vacuum at room temperature overnight giving the title product (11.11 g, 102%) as a dark brown oil. Mass spectrometry / gas chromatography indicated that the final compound was 100% pure; m / e: 219 (M + H) *.

EXAMPLE 2 Preparation of 3 - [(trismethyl) ethylenenaniline A mixture of the nitro compound 3 - [(trimethylsilyl) ethynyl] nitrobenzene prepared as described above (0.86 g, 3.92 mmol), in 2-propanol (30 ml), was degassed with nitrogen and treated with 5% platinum on alumina (268 mg). The mixture was stirred for 22 hours in a Parr apparatus under a hydrogen atmosphere (207 kPa). The reaction mixture was filtered through a short layer of Celite® (diatomaceous earth) and concentrated by evaporation to give an oil which was dried under vacuum overnight giving the title product (692 mg, 93%) in form of a yellowish brown oil. dH (300 MHz, CDCl 3): 0.24 (9H, s), 3.56 (2H, sa), 6.62 (1 H, ddd, J = 1.0, 2.3, 8.0), 6.78 (1 H, t, J = 2.2), 6.87 (1 H, dt, J = 7.7, 1.2), 7.07 (1 H, t, J = 7.8). dc (75.5 MHz, CDCI3): 93.4, 105.4, 115.6, 118.2, 122.4, 123.8, 129.2, 146.2. m / e: 190 (M + H) *. ^^ ^ ¿^ ^^ i¿¿¿ íia¿¿i? B ^^^ ^^ ¿¿^ ^ ^^ EXAMPLE 3 Preparation of monohydrochloride 6_7-bis (2-methoxyethoxy) -N-. { 3- r (methylmethoxy) ethynyl-phenyl-4-quinazolinamine May 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline (942 mg, 3.01 mmol) was treated with a solution of aniline (645 mg, 3.41 mmol) in 2-propanol (14 ml) and refluxed for 2.5 hours. The mixture was allowed to cool to room temperature and was stirred for 1 hour. The solid was collected by filtration, washed with 2-propanol (5 ml) and dried in vacuo overnight to give the title product (1.33 g, 88%) as a white solid. dH (400 MHz, CDCl 3): 0.21 (9H, s), 3.38 (3H, s), 3.41 (3H, s), 3.72 (2H, m), 3.77 (2H, m), 4.10 (2H, s), 4.53 (2H, s), 7.20 (1 H, t, J = 7.8), 7.23- 7.28 (2H, m), 7.75 (1 H, d, J = 7.8), 7.88 (1 H, s), 8.20 ( 1 H, s), 8.42 (1 H, s). m / e: 466 (M + H) *. EXAMPLE 4 Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride A suspension of the silyl compound monohydrochloride of 6,7-bis (2-methoxyethoxy) -N-. { 3 - [(trimethylsilyl) ethynyl] phenyl} -4-quinazolinamine prepared above (1.22 g, 2.43 mmol) in tetrahydrofuran (6.1 ml), treated with 1M fluroruro tetra (n-butyl) ammonium (2.6 ml, 2.55 mmol) solution tetrahydrofuran and stirred at room temperature for 1 hour. The solid was treated with 2-propanol (12.2 ml) and concentrated by evaporation. The oil in 2-propanol (20 ml) was treated with concentrated hydrochloric acid (0.2 ml) to give a precipitate. The mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 2-propanol (2 ml) and dried in vacuo to give the title product (747 mg, 72%) as a white solid (m.p. 226-229 ° C). dH (300 MHz, de-DMSO): 3.36 (6H, s), 3.77-3.80 (4H, m), 4.30 (1 H, s), 7.39 (1 H, s), 7.41 (1 H, d, J = 7.8), 7.50 (1 H, t, J = 7.9), 7.79 (1 H, d, J = 8.1), 7.88 (1 H, s), 8.40 (1 H, s), 8.86 (1 H, s ), 11.48 (1 H, sa). dc (100 MHz, de-DMSO): 58.4, 58.5, 68.7, 69.2, 69.7, 67.0, 81.3, 83.0, 100.3, 105.2, 107.2, 121.9, 125.4, 127.6, 128.9, 129.2, 135.2, 137.7, 148.3, 149.2, 155.4, 158.0. m / e: 394 (M + H) +.

EXAMPLE 5 Preparation of 4- (3-IT6.7-bis (2-methoxy-ethoxy-l-4-quinaznolpanophenyl) -2-methyl-3-butyn-2-ol monohydrochloride Refluxed for 5 hours 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline (15 g, 48 mmol), 4- (3-amino-phenyl) -2-methyl-3-butin-2- ol (9.2 g, 52.8 mmol) and acetonitrile (225 ml). The mixture was cooled to 5-10 ° C and stirred for 1 hour. The solid was collected by filtration and washed with v ». ^^ ********». , * «* ^ * ^ ... iriHiiiiMafrpii. ^^ .. ^, ^ ¿^ ^ ^ ^ ^ ^, acetonitrile (15 ml) and dried under vacuum overnight giving the title product (23.4 g, 100%) in the form of a white solid. dH (400 MHz, de-DMSO): 1.44 (6H, s), 3.31-3.32 (6H, m), 3.69-3.75 (4H, m), 4.24-4.30 (2H, m), 4.35-4.37 (2H, m), 7.25 (1 H, m), 7.39 (2 H, m), 7.72-7.74 (2 H, m), 8.47 (1 H, s), 8.79 (1 H, s), 11.64 (1 H, s) . m / e: 452 (M + H) +.

EXAMPLE 6 Preparation of 4-. { 3-r 6 -b, 2-methoxyethoxy) -4-quinazolinyl-amino. Phenyl} -2- methyl-3-butin-2-ol Monohydrochloride of 4- was stirred at room temperature. { 3 - [[6,7-bis (2-methoxyethoxy) -4-quinazol? Nil] amino] phenyl} -2-methyl-3-butin-2-ol prepared above (19.0 g, 39.7 mmol), water (95 ml) and ethyl acetate (380 ml) to form a mixture. The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide solution giving two clear layers. The organic layer was separated from the aqueous layer and concentrated in vacuo to a volume of approximately 190 ml. After a period of granulation in an ice bath, crystals of the title product were formed which were filtered and dried to give the product (15.13 g, 86%). dH (400 MHz, CDCl 3): 1.56 (6H, s), 3.35 (3H, s), 3.37 (3H, s), 3.7-3.71 (4H, m), 4.13-4.19 (4H, m), 7.0 (1 H, m), 7.13-7.17 (2H, m), 7.3 (1H, m), 7.6 (2H, m), 8.55 (1H, s). m / e: 452 (M + H) *.

EXAMPLE 7 Preparation of N- (3-ethynylphenyl) -6-bis.2-5-methoxyethoxy) -4-quinazolinamine monohydrochloride Monoochloride of 4- was stirred at room temperature. { 3- [[6,7-bis (2-methoxyethoxy) -4-qu] nazolinyl] amino] phenyl} -2-methyl-3-butin-2-ol prepared as described above (32.34 g, 66.3 mmol), water 10 (300 ml) and butan-1-ol (600 ml) to form a mixture. The pH of the mixture of 10-12 was adjusted with 50% aqueous sodium oxide solution giving two clear layers. The organic layer was separated from the aqueous layer and concentrated at atmospheric pressure whereby water was azeotropically separated from the butan-1-ol solution. The final volume of the butan-1-ol solution was approximately 300 ml. Anous solid sodium oxide was added to the azeotropically dried butan-1-ol solution and the resulting mixture was heated to reflux at 115-120 ° C for 24 hours. Butan-1-ol (150 ml) was removed by distillation and the concentrated reaction mixture was cooled to 15-25 ° C. Concentrated ochloric acid (6.1 ml) and butan-1-ol (60 ml) were added to the cooled concentrate and the mixture was granulated overnight at 20-25 ° C to establish the crystallization. By filtration, crystals of the title product were isolated which were vacuum dried at 45-50 ° C to remove butan-1-ol. Yield: 21.0 g, 73.7%. Purity by high performance liquid chromatography ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡(HPLC): 96.5%.

EXAMPLE 8 Preparation of N- (3-ethynylphenyl) -6- (2-methoxyethoxy) -4-quinazolinamine methanesulfonate Monoochloride of 4- was stirred at room temperature. { 3 - [[6,7-bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl} -2-methyl-3-butin-2-ol prepared above (32.34 g, 66.3 mmol), water (300 ml) and butan-1-ol (600 ml) to form a mixture. The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium oxide solution giving two clear layers. The organic layer was separated from the aqueous layer and concentrated at atmospheric pressure whereby water was azeotropically separated from the buta-1 -ol solution. The final volume of the butan-1-ol solution was approximately 300 ml. Anous solid sodium oxide (0.13 g, 3.3 mmol) was added to the azeotropically dried butan-1-ol solution and the resulting mixture was heated to reflux at 115-120 ° C for 24 hours. The reaction mixture was cooled to 15-25 ° C, methanesulfonic acid (4.6 ml) was added and the mixture was granulated overnight at 20-25 ° C to establish crystallization. By filtration, crystals of the title product were isolated and washed with butan-1-ol (25 ml) and dried in vacuo at 45-50 ° C to remove butan-1-ol. Yield: 29.16 g, 90%. Purity by HPLC: 96.7%. and ^^ w ^^^^^^^^ g ^^^ j ^^^^^^^ EXAMPLE Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4- monoochloride quinazolinamine They waved 4-. { 3 - [[6,7-bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl} -2-methyl-3-butyn-2-ol prepared above (20.0 g, 44.3 mmol), anous solid sodium oxide (0.09 g, 2.2 mmol) and butan-2-ol (400 mL) and heated to reflux at 100-102 ° C for 36 hours. The reaction mixture was cooled to 15-25 ° C and 0 concentrated ochloric acid (4.1 ml) was added. The resulting mixture was granulated overnight at 20-25 ° C to establish crystallization. By filtration, crystals of the title product were isolated and washed with butan-2-ol (25 ml) and dried under vacuum at 45-50 ° C to remove butan-2-ol. Yield: 17.7 g, 93%. Purity by HPLC: 99.1%. EXAMPLE 10 Preparation of N- (3-ethynylphenyl) -6-7-bis (2-methoxyethoxy-4-quinazolinamine monoochloride. 0 They waved 4-. { 3 - [[6,7-bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl} -2-methyl-3-butin-2-ol prepared above (20.0 g, 44.3 mmol), anous solid sodium oxide (260 mg, 6.5 mmol) and propan-2-ol (200 ml) and heated in a vessel pressure at 135-140 ° C during ^^^^^^^^^ m ^ ^ ^ bM? ^ ^? ^ ^ "MMfcM ^^. ^^ M ^^ - ^^^^^^ 23 hours. The reaction mixture was cooled to 60-65 ° C and concentrated ochloric acid (4.8 ml) was added. The resulting mixture was granulated overnight at 20-25 ° C to establish crystallization. The mixture was treated with water (10 ml), stirred at 58-60 ° C for 21 hours, cooled to 15-20 ° C and granulated for 2 hours. By filtration, crystals of the title product were isolated and washed with propan-2-ol (2x30 ml) and dried in vacuo at 45-50 ° C to separate the propan-2-ol. Yield: 17.6 g 92%.

EXAMPLE 11 Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride It was stirred 4-. { 3 - [[6,7-bis (2-methoxyethoxy) -4-quinazo-linyl] amino] phenyl} - 2-methyl-3-butin-2-ol prepared above (5.0 g, 11 mmol), hydroxide Solid anhydrous sodium (44 mg, 11 mmol) and 2-methoxyethanol (50 ml) and heated to reflux for 47 hours. The reaction mixture was cooled to 20-25 ° C and concentrated hydrochloric acid (1.1 ml) was added. The resulting mixture was granulated at 20-25 ° C for 1 hour to establish crystallization. By filtration, crystals of the title product were isolated which were washed with 2-methoxyethanol (10 ml) and dried under vacuum at 45-50 ° C to remove the 2-methoxyethanol. Yield: 3.73 g, 78%.

EXAMPLE 12 Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy-4-quinazolinamine methanesulfonate They waved 4-. { 3 [[6,7-bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl} -2-methyl-3-butin-2-ol prepared above (20.0 g, 44.3 mmol), anhydrous solid sodium hydroxide (0.09 g, 2.2 mmol) and butan-2-ol (400 mL) and heated to reflux at 100 -102 ° C for 36 hours. The reaction mixture was cooled to 15-25 ° C and methanesulfonic acid (5.1 g, 53.2 mmol) was added. The resulting mixture was granulated overnight at 20-25 ° C to establish crystallization. By filtration, crystals of the title product were isolated which were washed with butan-2-ol (25 ml) and dried under vacuum at 45-50 ° C to remove the butan-2-ol. Yield: 19.45 g, 90%. Purity by HPLC: 98.5%. EXAMPLE 13 Preparation of N- (3-ethylphenyl) -6-bis (2-methoxyethoxy) -4-quinazolinamine Heating at 78-82 ° C for 16 hours 4-chloro-6,7-bis (2- (methoxyethoxy) quinazoline (50 g, 160 mmol), 3-ethyl-aniline (21.34 g, 176 mmol) and propan 2-ol (500 ml). The mixture was cooled to 5-10 ° C and stirred for 1 hour. The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide solution giving two clear layers. The organic layer it was separated, washed with water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This oil was allowed to solidify and dried under vacuum at 20-25 ° C to give the title product (57.2 g, 90%) as a white solid. P. f. 72-74 ° C. dH (300 MHz, CDCl 3): 1.16 (3H, t, J = 7.6), 2.58 (2H, q, J = 7.6), 3.32 (3H, s), 3.34 (3H, s), 2.01-2.47 (2H, m), 2.08-2.54 (2H, m), 4.07-4.12 (4H, m), 6.91 (1H, d, J = 7.6), 7.11 (1H, s), 7.21 (1H, t, J = 7.8), 7.35 (1 H, s), 7.42 (1 H, s), 7.48 (1 H, d, J = 8.0), 8.13 (1 H, sa), 8.58 (1 H, s). dc (75.5 MHz, CDCI3): 15.4, 28.8, 59.1, 68.2, 68.9, 70.4 70.8, 103.0, 108.3, 109.3, 119.7, 121.7, 123.9, 128.8, 138.6, 145.1, 147.0, 148.6, 153.6, 154.4, 156.9. vmax (KBr, cm "1): 3,136 (s), 1,624 (s), 1,575 (s), 1,535 (s), 1, 487 (s). m / z: 398 (M + H) +. : C 65.64, H 6.96, N 10.32, C22H27N3O4 0.25H2O requires C 65.73, H 6.90, N 10.45%.

EXAMPLE 14 Preparation of N- (3-ethylphenyl) -6- (2-methoxyethoxy) -7-benzyloxy-4-quinazolinamine Warm at 150-152 ° C for 23 hours N- (3-ethyl-phenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine prepared as described above (4.0 g, 10 mmol), hydroxide sodium solid anhydrous (104 mg, ^ G¡gjg 2.6 mmoles) and benzyl alcohol (20 ml). The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate / hexane as eluent to give a white solid which was dried under vacuum at 45-50. ° C giving the product of the title (2.52 g, 58%). P. f. 156-157 ° C. dH (300 MHz, CDCl 3): 1.17 (3H, t, J = 7.6), 2.58 (2H, q, J = 7.6), 3.33 (3H, s), 3.65-3.68 (2H, m), 4.07-4.11 ( 2H, m), 5.11 (2H, s), 6.93 (1H, d, J = 7.7), 7.18-7.29 (5H, m), 7.35-7.42 (4H, m), 7.50 (1H, d, J = 8.0), 8.20 (1 H, sa), 8.61 (1 H, s). 10 dc (75.5 MHz, CDCI3): 14.2, 15.4, 28.8, 59.2, 69.2, 70.7, 70.8, 103. 2, 109.1, 109.4, 119.7, 121.7, 124.0, 127.3, 128.1, 128.5, 128.8, 135.8, 138.6, 145.1, 147.0, 148.9, 153.7, 154.2, 156.9. vmax (KBr, cnT1): 1.625, 1.61 1, 1.576. m / z: 430 (M + H) +. 15 Analysis found: C 71.42: H 6.50; N 9.48. C 26 H 27 N 3 O 3 requires C 72.70; H 6.34; N 9.78%.

EXAMPLE 15 Preparation of N- (3-ethylphenyl) -6- (2-methoxyethoxy) -7-butyloxy-4-quinazolinamine N- (3-Ethylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolineamine prepared above (4.0 g, 10 mmol) was heated at reflux for 12 days. anhydrous solid sodium hydroxide (94 g, 2.36 mmol) and butan-1-ol (20 ml). The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate / hexane as eluent to give a white solid which was dried in vacuo at 45-50. ° C giving the product of the title (2.57, 65%). P. f. 90-92 ° C. dH (300 MHz, CDCl 3): 0.93 (3H, t, J = 7.4), 1.19 (3H, t, J = 7.6), 1.45 (2H, sextet, J = 7.5), 1.79 (2H, pentete, J = 6.9 ), 2.61 (2H, q, J = 7.6), 3.39 (3H, s), 3.70-3.74 (2H, m), 4.00 (2H, t, J = 6.6), 4.12-4.15 (2H, m), 6.94 (1 H, d, 10 J = 7.7), 7.15 (1 H, s), 7.24 (1 H, t, J = 7.8), 7.34 (1 H, s), 7.44 (1 H, s), 7.51 ( 1 H, d, J = 8.0), 7.95 (1 H, sa), 8.60 (1 H, s). dc (75.5 MHz, CDCI3): 13.8, 15.4, 19.2, 28.8, 30.8, 59.3, 68.7, 69.3, 70.9, 103.2, 108.2, 108.9, 119.6, 121.6, 124.0, 128.9, 138.6, 145.2, 147.2, 148.8, 153.6, 154.9, 156.8. 15 vmax (KBr, cm-1): 1,618, 1,576, 1,519. m / z: 396 (M + H) +. Analysis found: C 70.90; H 7.56; N 10.66. C23H29N3O3 requires C 69.85; H 7.39; N 10.63%. l tete .. ... .... ^. ^ ¿^ ^ ^^^^^ A ^^ at .- ^^.

EXAMPLE 16 Preparation of N- (4-methoxyphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine 4-Chloro-6,7-bis (2-methoxyethoxy) quinazoline (25 g, 79.9 mmol), 4-anisidine (9.8 g, 79.9 mmol) and propan-2 were heated at 78-82 ° C for 16 hours. ol (250 ml). The mixture was allowed to cool to 5-10 ° C and was stirred for 1 hour. The solid was collected by filtration and washed with propan-2-ol (25 ml). The isolated solid was recrystallized from ethanol / water and dried overnight at 40-105 ° C in a vacuum oven. The recrystallized solid was mixed with water (100 ml) and ethyl acetate (250 ml). The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide solution giving two clear layers. The organic layer was separated, washed with water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid which was dried under vacuum at 40-45 ° C giving the product of the title (20.86 g, 65%). P. f. 186-187 ° C. dH (300 MHz, CDCl 3): 3.31 (3H, s), 3.35 (3H, s), 3.62-3.65 (2H, m), 3.70-3.72 (2H, m), 3.74 (3H, s), 4.04-4.11 (4H, m), 6.83 (2H, d, J = 9.0), 7.09 (1 H, s), 7.33 (1 H, s), 7.46 (2H, d, J = 9.0), 8.12 (1 H, s) ). 20 dc (75.5 MHz, CDCI3): 55.4, 59.2, 68.2, 69.0, 70.4, 70.8, 103.1, 108.3, 109.1, 114.2, 124.7, 131.4, 146.8, 148.6, 153.7, 154.3, 156.7, 157.3. vmax (KBr, cm-1): 1 -619, 1.590, 1.582, 1.51 1. m / z: 400 (M + H) +. ^^^ i. ^^^^ to .. ^. ^^^. g jßM BgjgE g j ^ ¡¡Analysis found: C 63.30; H 6.37; N 10.47. The C2? H25N3O5 requires C 63.42; H 6.31; N 10.52%.

EXAMPLE 17 Preparation of N- (4-methoxyphenyl) -6- (2-methoxyethoxy) -7-benzyloxy-4-quinazolineamine The N- (4-methoxy-phenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolineamine prepared above (2.0 g, 4.6 mmol), hydroxide were heated at 145-150 ° C for 18 hours. anhydrous solid sodium (104 mg, 2.6 mmol) and benzyl alcohol (20 ml). The reaction mixture was allowed to cool to room temperature and was purified by column chromatography on silica gel using a gradient system with ethyl acetate / hexane as eluent, giving a white solid which was dried at 45-50 ° C at vacuum giving the product (0.915 g, 42%). P. f. 208-209 ° C. dH (300 MHz, CDCl 3): 3.34 (3H, s), 3.91 (2H, t, J = 4.2), 3.74 (3H, s), 4.10 (2H, sa), 5.13 (2H, s), 6.83 (2H , d, J = 8.9), 7.20-7.30 (5H, m), 7.36-7.38 (3H, m), 7.47 (2H, d, J = 8.9), 8.10 (1H, sa), 8.54 (1H, s). dc (75.5 MHz, CDCI3): 55.5, 59.3, 69.2, 70.7, 70.9, 103.3, 109.0, 109.1, 114.2, 124.6, 127.3, 128.1, 128.5, 131.3, 135.8, 146.8, 148.8, 153.7, 154.2, 154.2, 156.8, 157.2. vmax (KBr, cm-1): 1,619, 1,580, 1,511. m / z: 432 (M + H) +.

IÉÉMÍLZÍ - »-. lMílÉfllfflílf •. «^ awaAa ^ jfc ^ to ^ taaMgaah Analysis found: C 69.48; H 5.85; N 9.68. C25H25N3O4 requires C 69.59; H 5.84; N 9.74%.

EXAMPLE 18 Preparation of N-phenyl-N-methyl-6,7-bis (2-methoxyethoxy) -4-quina-zolinamine 24-Hour 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline (10 g, 31.97 mmol), N-methyl-aniline (3.5 mL, 31.97 mmol) and acetonitrile (100 mg) were heated at 78-82 ° C for 24 hours. ml). The mixture was allowed to cool to 5-10 ° C and was stirred for 0.5 hours. The solid was collected by filtration and dried at 50-55 ° C for 5 hours in a vacuum oven. The isolated solid was mixed with water (50 ml) and ethyl acetate (200 ml). The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide solution giving two clear layers. The organic layer was separated, washed with water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid which was dried under vacuum at 50-55 ° C to give the product of the title (8.55 g, 70%). P.F. 109-111 ° C. dH (300 MHz, CDCl 3): 3.33 (3H, s), 3.39 (3H, s), 3.42-3.45 (2H, m), 3.48-3.51 (2H, m), 3.58 (3H, s), 3.74 -3.78 (2H, m), 4.16-4.20 (2H, m), 6.33 (1H, s), 7.11-7.20 (4H, m), 7.83 (2H, t, J = 7.8), 8.68 (1H, s). dc (75.5 MHz, CDCI3): 42.0, 59.2, 59.3, 67.6, 68.2, 70.3, 70.4, 106.5, 107.9, 110.9, 125.8, 126.0, 129.9, 147.0, 148.4, 148.7, 153.0, 153.4, 160.4. jfr'tf max (KBr, cm'1): 1,615, 1,571, 1,497. m / z 384 (M + H) +. Analysis found: C 65.85; H 6.52; N 11.01. C 21 H 25 N 3 O 4 requires C 65.78; H 6.57; N 10.96%.

EXAMPLE 19 Preparation of N-Phenyl-N-methyl-6-.2-methoxyethoxy) -7-butyl-oxy-4-quinazolinamine 24-N-methyl-N-phenyl-6,7-bis (2-methoxyethoxy) -4-quinazolineamine prepared as described above (1.0 g, 2.61 mmol), anhydrous sodium hydroxide (97.5 mg, 2.43 mmole) and butan-1-ol (10 ml). The reaction mixture was allowed to cool to room temperature and was purified by column chromatography on silica gel using a gradient system with ethyl acetate / hexane as eluent to give a white solid which was dried at 45-50 ° C. vacuum giving the title product (517 mg, 52%). P.F. 62-63 ° C. dH (300 MHz, CDCl 3): 0.93 (3H, t, J = 7.4), 1.45 (2H, sextet, J = 7.4), 1.80 (2H, pentete, J = 6.7), 3.35 (H, s), 3.44- 3.52 (4H, m), 3.59 (3H, s), 4.05 (2H, t, J = 6.7), 6.34 (1H, s), 7.12-7.21 (4H, m), 7.34 (2H, t, J = 7.7), 8.69 (1 H, s). dc (75.5 MHz, CDCI3): 13.8, 19.2, 30.7, 42.0, 59.2, 67.8, 68.6, 70.4, 106.5, 107.7, 110.6, 125.8, 125.9, 129.9, 147.0, 148.6, 153.0, 153.8, _M¡ _ »_ &ji§ áá_gib í | ^ Si £ tó ¡Mgi ¡? 160.4. - #? vmax (KBr, cm "1): 1616, 1572, 1543. m / z 382 (M + H) + Analysis found: C 69.39, H 7.38, N 10.86, C22H27N3O3 requires C 69.27, H 7.14, N 11.02% .

^^ H Z? * < ^ * 2 * ~ *. -. ^ - ^ - ^ a¿H

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing a compound of formula 1 1 or a pharmaceutically acceptable salt or solvate of said compound, formula wherein: each of R1 and R2 is independently selected from C1-C10 alkyl and C1-C10 alkoxy, wherein said alkyl and alkoxy are optionally substituted with up to 2 substituents independently selected from hydroxy and Ci-Cβ alkoxy and R15 is H, C1-C10 alkyl or - (CH2) q (aryl Ce-Cio), wherein q is an integer from 0 to 4, which process comprises treating a composed of formula 2 wherein R? 5) R1 and R2 are as defined above and G is a selected blocking group of -C (OH) R3R4 and -SiR3R4R5, wherein each of R3, R4 and R5 is independently CrC6 alkyl, with (a) an alkali metal or alkaline earth metal hydroxide in a solvent comprising C1 alkyl -C.sub.10 hydroxy-substituted, when G is -C (OH) R3R4, or (b) a tetrahydric (C? -C6 alkyl) ammonium fluoride compound in an aprotic solvent, when G is - SiR3R4R5. 2. The method according to claim 1, wherein

G is -C (OH) R3R4, said solvent is a secondary alcohol and said alkali metal or alkaline earth metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide.

3. The process according to claim 2, wherein said solvent is butan-2-ol or isopropanol or a mixture of the two solvents and said alkali metal or alkaline earth metal hydroxide is sodium hydroxide.

4. The method according to claim 1, wherein G is -SiR3R4R5, said tetra (C? -C6 alkyl) ammonium fluoride compound is tetra (n-butyl) ammonium fluoride and said aprotic solvent is selected from tetrahydrofuran, diethyl ether, dimethoxyethane, toluene, dichloromethane, chloroform and a mixture of two or more of the aforementioned solvents.

5. The process according to claim 1, wherein R1 and R2 are 2-methoxyethoxy and R15 is H.

6. The process according to claim 1, wherein said compound of formula 2 is prepared by treating a compound of formula 3 wherein R1 and R2 are as defined in claim 1, with a compound of formula 4 wherein R15 and G are as defined in claim 1.

7. The process according to claim 6, wherein the compound of formula 3 is treated with the compound of formula 4 in an organic solvent selected from dimethylformamide, dimethisulfoxide, tetrahydrofuran, acetonitrile and a mixture of two or more of the aforementioned solvents.

8. The process according to claim 7, wherein said solvent is acetonitrile, R1 and R2 are 2-methoxyethoxy and R15 is H.

9. The process according to claim 6, wherein the compound of formula 3 is prepared by treating a compound of formula 5 ^ gg ^ & »v, < g - ¿i *? i ^ j ^^^ ^ yij ^^ ^ W ^^ with thionyl chloride in anhydrous dichloromethane.

10. The process according to claim 9, wherein R1 and R2 are 2-methoxyethoxy.

11. A process for preparing a compound of formula 6 or 7 or a pharmaceutically acceptable salt or solvate thereof, formulas in which: R6 is C10 alkyl or - (CH2) mO (CH2) nCH3, R7 is C1-C10 alkyl or - (C6-C6 alkyl) (C6-aryl) C? O), in which the aforementioned R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (C? -C6 alkyl) sulfonyl, C? Alkyl, C? -C6 alkoxy , C 6 -C 0 aryloxy or (C 6 -C 6 aryl) sulfonyl, each m is independently an integer from 1 to 6 and n is an integer from 0 to 3, R 15 is H, C 1 -C 10 alkyl O - ( CH2) q (aryl C6-C? O), wherein q is an integer from 0 to 4, which process comprises treating a compound of formula 8 wherein R6 and R15 are as defined above and G1 is - C (OH) R3R4 wherein each of R3 and R4 is independently C C6, with a primary or secondary alcohol of formula R7-OH, wherein R7 is C1-C10 alkyl or (CrC6 alkyl) (C6-C? 0 aryl), the above-mentioned R7 groups being optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (Cr C6 alkyl) ) sulfonyl, C-C-alkyl, C-C-alkoxy, C6-C6-aryloxy and (C6-C6-alkylsulfonyl), in the presence of an alkali metal or alkaline earth metal hydroxide.

12. The process according to claim 11, wherein said alkali metal or alkaline earth metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide.

13. The method according to claim 12, wherein said alkali metal hydroxide or alkaline earth metal is sodium hydroxide, R6 is H, R15 is 2-methoxyethoxy and said alcohol of formula R7 -OH is an alcohol secondary. ** ±? 3t * a *** to * * .- * *. MfflíÉlÉifii ^^^

14. - A process for preparing a compound of formula 9 or a pharmaceutically acceptable salt or solvate thereof, formula wherein: R6 is alkyl C.-Co or - (CH2) mO (CH2) nCH3, R7 is C1-C.0 alkyl or- (C6-C6 alkyl) (Ce-Cι aryl), in which the aforementioned R 7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (Ci-C 1 -sulfonyl alkyl, C β β alkyl, CrC 6 alkoxy, C 6 aryloxy C 0 and (C 6 -C 6 aryl) sulfonyl, each m is independently an integer from 1 to 6 and n is an integer from 0 to 3, each of R 8, R 9 and R 10 is independently selected from H, alkyl C1-C10, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR11, -C (O) R11, -C (O) OR11, -NR12C (O) OR14, -OC (O) R11, - NR12SO2R14, -SO2NR11R12, -NR12C (O) R11, -C (O) NR11R12, -NR11R12, -S (0) j (CH2) q (aryl Cedo), -S (O) j (C alkyl SCs), in where j is an integer from 0 to 2, - (CH2) q (aryl C6-C10), -O (CH2) q (aryl C6-C? 0), -NR12 (CH2) q (aryl C6-C) ? 0) and - (CH2) q (group h 4-10 membered heterocyclic), where q is an integer from 0 to 4; optionally containing said alkyl group 1 or 2 heteroorrests selected from O, -S (O) r, wherein j is an integer from 0 to 2, and -N (R12) -, with the proviso that two O atoms , two S atoms or one -¡¿s HH "^^ ^ ^ i &.. ^^^^^^ J ^ O atom and S atom are not attached directly to each other; being optionally fused aryl groups and said heterocyclic aryl group with C6 -C? O, a saturated cyclic Cs-Cβ group or a heterocyclic group of 4-10 members, and the said alkyl, aryl and heterocyclic groups being optionally substituted with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR12SO2R14, -SO2NR11R12, -C (O) R11, -C (O) OR11, -OC (O) R11, -NR12C (O) OR14, -NR12C (O) R11, -C ( O) NR11R12, -NR11R12, -OR11, C1-C10 alkyl, - (CH2) q (C6-C 0) and - (CH2) q (4-10 membered heterocyclic group), where q is a integer that varies from 0 to 4, each R11 is independently selected from H, C1-C10 alkyl, - (CH2) q (aryl Ce-Cio) and - (CH2) q (heterocyclic group of 4-10 members), in those that q is an integer that varies from 0 to 4, optionally including the aforementioned gr upo alkyl 1 or 2 heteroorrests selected from O, -S (O), wherein j is an integer from 0 to 2, and -N (R12) -, with the proviso that two O atoms, two S atoms or an atom O and an atom S are not directly connected to each other; the said aryl and heterocyclic groups R11 being optionally condensed with C6-C6 aryl group, a saturated C5-C8 cyclic group or a 4-10 membered heterocyclic group; and the aforementioned R11 substituents being optionally substituted, except H, with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R12, -C (O) OR12, - OC (O) R12, -NR12C (O) R13, -C (O) NR12R13, -NR12R13, hydroxy, alkyl C.-C6 and alkoxy CrC6, each of R12 ^^^^ l ^^ g ^ j ^ g ^ ^ and R13 is independently H or Ci-Cß alkyl, R14 is selected from fgsg »substituents indicated in the definition of R11, except H, R15 is H; I rent

C1-C10 or - (CH2) q (aryl C6-C? 0), wherein q is an integer from 0 to 4, which process comprises treating a compound of formula 10 10 wherein R15, R6, R8, R9 and R > 1'0u are as defined above, with a primary or secondary alcohol of the formula R7-OH; in R7 is C1-C10 alkyl or (CrC6 alkyl) (Ce-Cio aryl), the above-mentioned R7 groups being optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (CrC6 alkyl)

Sulfonyl, C-C-alkyl, C-C-alkoxy, Ce-C-aryloxy and (C6-C6-C) o-sulfonyl aryl, in the presence of an alkali metal or alkaline earth metal hydroxide. 15. The process according to claim 14, wherein said alkali metal or alkaline earth metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, 20 magnesium hydroxide and potassium hydroxide. 16. The process according to claim 15, wherein said alkali metal or alkaline earth metal hydroxide is sodium hydroxide and said alcohol of formula R7-OH is a primary alcohol.

17. - A compound of formula 2 wherein: each of R 1 and R 2 is independently selected from C 1 -C 10 alkyl and C 1 -C 10 alkoxy, wherein said alkyl and alkoxy are optionally substituted with up to 2 substituents independently selected from hydroxy and Ci-Cβ alkoxy, is a blocking group selected from -C (OH) R3R4 and -SiR3R4R5, each of R3, R4 and R5 is independently C1-C6 alkyl and R15 is H, C1-C10 alkyl or - (CH2) q (C6-C aryl ? 0), where q is an integer from 0 to 4.