MX2008004178A

MX2008004178A - Chemical process

Info

Publication number: MX2008004178A
Application number: MXMX/A/2008/004178A
Authority: MX
Inventors: John Hogan Philip; David Pittam John; Blixt Jorgen; David Golden Michael; Michael Glanville Martin David; Patel Zakariya; Joseph Sependa George; John Squire Christopher; Cartwright Alexander Wright Nicholas; Joseph Montgomery Francis
Original assignee: Astrazeneca Ab
Priority date: 2005-09-30
Filing date: 2008-03-27
Publication date: 2008-09-02

Abstract

The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4- bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.

Description

CHEMICAL PROCESS The present invention relates to chemical processes for the manufacture of certain chenazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of quinazoline derivatives and processes for the manufacture of quinazoline derivatives using said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpypyren-4-ylmethoxy) quinazoline. This compound falls within the broad description of WO 98/1 3354 and is exemplified in WO 01/32651, in Examples 2a, 2b and 2c. The compound 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline is described herein by means of Formula I: and as ZD6474, the code number by which the compound is known. The compound ZD6474 is also known as Vandetanib and as ZactimaM R. Normal angigenesis plays an important role in a variety of processes including embryonic development, wound healing and various components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma (Fan et al., 1 995, Trends Pharmacol., Sci. 16: 57-66; Folkman , 1 995, Nature Medicine 1: 27-31). It is thought that the alteration of vascular permeability plays a role in both normal and pathological physiological processes (Cullinan-Bove et al., 1993, Endocrinology 1 33: 829-837, Senger et al., 1 993, Cancer and Metastasis Reviews, 12 : 303-324). Several polypeptides with endothelial cell growth promoting activity in vitro have been identified including, acidic and basic fibroblast growth factors (aFGF &bFGF) and vascular endothelial growth factor (VEGF). By virtue of the restricted expression of its receptors, the activity of VEGF growth factor, in contrast to that of FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 193, Endocrinology, 1 33: 848-859, Kolch et al, 1995, Breast Cancer Research and Treatment, 36: 1 39-1 55) vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 2001 7-20024). Antagonism of VEGF action by sequestering VEGF with antibody can result in inhibition of tumor growth (Kim et al, 1 993, Nature 362: 841-844). The receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals through the plasma membrane of cells.These transmembrane molecules characteristically consist of an extracellular ligand binding domain connected through a segment in the plasma membrane to a Intracellular tyrosine kinase domain Ligand binding to the receptor results in the stimulation of the receptor-associated tyrosine ciansa activity, which leads to the phosphorylation of tyrosine tato residues in the receptor like the other intracellular molecules. tyrosine phosphorylation initiate a signaling cascade that leads to a variety of cellular responses.To date, at least nineteen different RTK subfamilies, defined by amino acid sequence homology, have been identified. tyrosine kinase receptor similar to fms, Fit-1 (also referred to as VEGFR-1), the receptor containing kinase insertion domain, KDR (also referred to as VEGFR-2 or Flk-1) and another receptor tyrosine kinase similar to fms. Flt-4. Two of these related RTKs, Flt-1 and KDR, have been shown to bind VEGF with high affinity (De Vries et al., 1992, Science 255: 989-991, Terman et al., 1992, Bíochem. Biophys. Res. Comm. 192, 187: 1579-1 586). The binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes. VEGF is a key stimulus for vasculogenesis and angiogenesis.

This cytokine induces a vascular bud phenotype by inducing endothelial cell proliferation, protease expression and migration and subsequent organization to form a capillary tube (Keck, PJ, Hauser, SD, Kirvi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, DT, Science (Washington DC), 246: 1309-1312, 1989; Lamoreaux, WJ, Fitzgerald, ME, Rener, A., Hasty, KA, and Charles, ST, Microvasc. Res., 55: 29-42, 198; Pepper MS, Mntesano, R., Mandroita, SJ, Ore, L. Vassalli, JD, Enzyme Protein, 49: 138-162 1996). In addition, VEGF induces significant vascular permeability (Dvorak, HF, Detmar, M., Claffey, KP, Nagy, JA, van de Water, L., and Senger, DR, (Int. Arch. Allerg Immunol., 107: 233 -235, 195; Bates, DO, Heald, R.IK., Curry.FE and Williams, BJ Physiol. (London)., 533: 263-272, 201), promoting the formation of an immature vascular network, hyper- permeable, which is characteristic of pathological angiogenesis It has been shown that activation of KDR alone is sufficient to promote all major phenotypic responses to VEGF, including endothelial cell proliferation, migration and survival, and the induction of vascular permeability (Meyer, M., Clauss, M., Lepple-Wienhues, A., Waltenberger, J., Augustin, HG, Ziche, M., Lanz, C, Büttner, M., Rziha, HJ., And Dehio, C, EMBO J ., 18: 363-374, 1999; Zeng, H., Sanyal, S. and Mukhopadhyay, D., J. Biol. Chem., 276: 32714-32719, 2001; Gille, H., Kowalski, J., Li, B., LeCouter, J., Moffat, B, Zioncheck, TF, Pelleti er, N. and Ferrara, N., J. Biol. Chem., 276: 3222-3230, 2001). ZD6474 is a potent inhibitor of VEGF RTK and also has some activity against epidermal growth factor (EGF) RTK. ZD6474 inhibits the effects of VEGF and is of interest for its vascular permeability and / or anti-angiogenic effects. Angiogenesis and / or an increase in vascular permeability is present in a wide range of disease states including cancer (including leukemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, Kaposí's sarcoma, hemangioma, acute and chronic nephropathies , atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, lymphedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with proliferation of retinal vessels including age-related macular degeneration. ZD6474 has been shown to elicit amylo spectrum antitumor activity in a range of models following oral administration once a day (Wedge SR, Ogilvie DJ, Dukes M. et al, Proc. Am. Assoc. Canc. Res. 2001; 42: abstract 31 26). WO 98/1 3354 describes several possible routes for preparing 4-anilino quinazoline compounds. However, there is no specific description in WO 98/13354 of a process for preparing a compound of Formula I. WO 98/1 0767 also describes several possible routes for preparing 4-anilino quinazoline compounds. However, there is no specific description in WO 98/1 0767 of a process for preparing a compound of Formula I. WO 01/32651 describes several alternative routes to prepare a compound of Formula I.

The route that is described in Example 2a of WO 01/32651 involves the reaction of the compound 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (piperidin-4-ylmethoxy) quinazoline with aqueous formaldehyde, followed by sodium cyanoborohydride in a mixture of tetrahydrofuran and methanol solvents. The product is purified by chromatography and isolated as the free base. The free base is then converted to the hydrochloride salt by reaction with hydrogen chloride in a mixture of methylene chloride and methanol solvents. The route described in Example 2b of WO 01/32651 involves the reaction of the compound 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1 - (tert-butoxycarbonyl) piperidin-4 -lmetoxy) quinazoline with aqueous formaldehyde in formic acid, followed by reaction with sodium hydroxide in water and extraction of the product with ethyl acetate. The product is in the form of the free base. The route that is described in Example 2c of WO 01/32651 involves the reaction of the compound 4-chloro-6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline with 4-bromo-2-fluoroaniline and hydrogen in isopropanol. The product that is isolated is in the form of the hydrochloride salt. In an NMR experiment, the hydrochloride salt is dissolved in dimethylsulfoxide and converted to the free base by adding solid potassium carbonate. The free base is then converted to the tpfluoroacetate salt by adding trifluoroacetic acid. In another experiment, the hydrochloride salt is suspended in methylene chloride and washed with saturated sodium hydrogen carbonate to provide the free base.WO 01/32651 also discloses routes for preparing the starting materials that are used in Examples 2a, 2b and 2c, such as the compounds 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (piperidin- 4-ylethoxy) quinazoline, 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1 - (tert-butoxycarbonyl) pyridin-4-ylmethoxy) quinazoline and 4-chloro-6-methoxy-7 - (1-methylpiperidin-4-ylmethoxy) quinazoline. Several of these routes are discussed in more detail below. The routes described in WO 01/32651 for preparing ZD6474 (such as the hydrochloride salt or the free base) are also described and / or referred to in publications that relate to combination therapies including ZD6474, such as, WO 03/039551, WO 2004/014383, WO 2004/014426, WO 2004/032937, WO 2004/071 397 and WO 2005/004870. Existing routes for preparing the compound of Formula I are satisfactory for the synthesis of relatively small amounts of the compound. However, the routes involve linear rather than convergent synthesis, requiring the use of multiple purification steps and the isolation of a substantial number of intermediaries.

As such, the overall yield of the synthesis is not high. Therefore, there is a need for a more efficient synthesis of the compound of Formula I suitable for use to make larger amounts of that compound. There is also a need for more efficient synthesis of intermediary compounds useful in the synthesis of the compound of Formula I to be used to make larger amounts of those intermediate compounds. Preferably, the new syntheses should minimize the number of intermediate compounds that need to be isolated and should not involve expensive and slow purification procedures. Additionally, the new syntheses should consistently form high quality compounds, particularly in order to form a high quality compound of Formula I to meet the high purity requirements of a pharmaceutical product. The new syntheses should also use procedures and reagents that can be used safely in a manufacturing plant and that comply with environmental guidelines. In accordance with the present invention, we now provide improved processes for the manufacture of ZD6474, the compound of Formula I: In accordance with the present invention, the processes are also provided for the manufacture of intermediates which can be used in the manufacture of ZD6474. The new processes are advantageous because they allow the compounds to be made in high quality and high performance on a larger scale. The processes allow a substantial reduction in the number of intermediary compounds that must be isolated and, in general, are more convergent than the previous routes. Such changes provide significant advantages of time and cost. So that there is no doubt, the term "ZD6474" as used herein, refers to the free base ZD6474, unless stated otherwise. A key intermediate that can be used in the preparation of ZD6474 is a compound of Formula I wherein R is a suitable sulfonate ester, such as mesylate, esylate, besylate or tosylate. In a further embodiment, the compound of Formula I is 1- (tert-butoxycarbonyl) -4- (4-methylphenylsulfonyloxymethyl) piperidine, the compound of Formula II: II Example 2 of WO 01/32651 describes a route for the preparation of a compound of Formula I I. The route involves the reaction of ethyl 4-piperidinecarboxylate with di-tert-butyl dicarbonate in an ethyl acetate solvent to provide ethyl 4- (1- (tert-butoxycarbonyl) piperidine) carboxylate, which is isolated. The 4- (1 - (tert-butoxycarbonyl) pyperidine) ethyl carboxylate is then reacted with lithium aluminum hydride in tetrahydrofuran to provide 1- (tert-butoxycarbonyl) -4-hydroxymethylpiperidine, which is isolated. The 1 - (tert-butoxycarbonyl) -4-hydroxymethylpiperidine is then reacted with 1, 4-diazabicyclo [2.2.2] octane and toluene sulfonyl chloride in a solvent of tert-butyl methyl ether to provide the compound of the Formula II: EP-A-0317997 describes a route for the preparation of a compound of the Formula II. The route involves the reaction of 4-carboxypiperid(also known as isonipecotic acid) with sodium carbonate and di-tert-butyl dicarbonate in an aqueous solvent to provide 4-carboxyl-piperidin-1-carboxylic acid tert-butyl ester, which is isolated. The 4-carboxy-piperidin-1-carboxylic acid tert-butyl ester is then reacted with borane in a tetrahydrofuran solvent to provide the compound of Formula I I. WO 94/27965 describes a route for the preparation of a compound of Formula I I. The route entails the reaction of 4-hydroxymethylpiperidwith di-tert-butylcarbonate in a tetrahydrofuran solvent to provide 4- (hydroxymethyl) piperidin-1-tert-butylcarboxylate, which is isolated as an oil. The 1 - (tert-butoxycarbonyl) -4-hydroxymethylpiperidis then reacted with toluene sulfonyl chloride and pyridto provide the compound of Formula I I. The routes described in the prior art documents for the preparation of a compound of Formula I I are satisfactory for the synthesis of relatively small amounts of the compound. However, they all require that each of the intermediaries be isolated and, therefore, include multiple isolation and / or purification steps. This results in a satisfactory overall yield of the compound of Formula I I on the small scale used. However, the routes described in the prior art documents are not suitable for use in a manufacturing scale because they include multiple isolation and / or purification steps, which can not be conducted efficiently on a manufacturing scale . In particular, the routes described in the prior art documents are not suitable for use in the manufacture of a high purity pharmaceutical product. Therefore, there is a need for a more efficient synthesis of a compound of Formula I I suitable for use in making large amounts of that compound. Preferably, the new syntheses should not involve expensive and slow isolation and / or purification procedures. In this way, the new synthesis should reduce the number of isolation and / or purification procedures required, thereby reducing costs and manufacturing times. Preferably, the new synthesis should minimize the number of solvents used throughout the process, which improves environmental performance and provides the opportunity for solvent recovery. Preferably, the new synthesis should also provide a strong and reliable method of isolating the compound of Formula II and should consistently provide high-quality compound of Formula II, for example, in order to meet the regulatory requirements for introduction of starting materials in the production of pharmaceutical products. According to a first aspect of the present invention, there is provided a process for the manufacture of a compound of the Formula Ha from a compound of (C1-C6) alkyl-4-piperidarboxylate of the Formula I: (C1-C6) alkyl III; said process comprises the steps of: (a) reacting the (C1-C6) alkyl-4-piperidinecarboxylate compound of Formula III with di-tert-butyl dicarbonate in the presence of toluene or xylene to form a first mixture comprising toluene or xylene, tert-butanol and a compound of the Formula IV: (C1-C6) alkyl IV; (b) substally removing the tert-butanol from the first mixture; (c) reacting the compound of Formula IV with a suitable reducing agent in situ in the presence of toluene or xylene to form a second mixture comprising toluene, reduction by-products including by-products of alcohol and a compound of the Formula V: V; (d) substally removing the alcohol by-products of the second mixture; and (e) reacting the compound of Formula V with a suitable sulfonylating agent in situ to form a sulfonate ester in the presence of a suitable base and toluene to form the compound of the Formula Na: Where R is a suitable sulfonate ester, such as, mesylate, esylate, besylate or tosylate. In one embodiment, the sulfonating agent is tosyl chloride. So that there is no doubt, the term "in sítu" means that the reaction was ralizada without isolation of the reagents of the step of previous process. The process of the first aspect of the present inven is advantageous because it allows to make a compound of the Formula Na in high quality and high performance on a larger scale. Normally, each of the steps of the process of the first aspect of the present inven proceeds in more than 95% yield.

All process steps of the first aspect of the present inven are conducted in toluene or xylene as the solvent. In another embodiment, all steps of the first aspect of the present inven are conducted in toluene. This allows the process to be conducted as a couous process without isolation and / or purification of the intermediate compounds of Formulas IV and V. This significantly reduces the time and cost of manufacturing the compound of Formula I on a larger scale. The use of a single solvent, such as toluene or xylene, can also allow for solvent recycling, which increases the process efficiency and provides environmental benefits. The use of toluene or xylene as the solvent also allows the efficiency and convenient removal of reactive by-products (such as alcohols), for example, by distillation. The presence of such reactive by-products could lead to impurities in the compound of Formula Ia if it is not removed at the appropriate time.

Additionally, the use of toluene or xylene as the solvent in the process of the first aspect of the present inven allows convenient isolation of the compound of Formula I by the crystallization. The compound of Formula I may, for example, be isolated more than 99.5% pure by crystallization directly from the reaction mixture without the need for further purification. This is advantageous, for example, when the compound of the Formula Na is to be introduced in the last step in the production of a pharmaceutical product, for example, a compound of Formula I, because it minimizes the risk of impurities being introduced. in the pharmaceutical product. Step (a) of the process uses a (C 1 -C 6) alkyl-4-piperidinecarboxylate compound of Formula I 1, in particular a (C 1 -C 4) alkyl-4-piperidinecarboxylate compound of Formula I 1. In particular, a compound of (C 1 -C 6) alkyl-4-piperidinecarboxylate of Formula III which may be used in step (a) may be, for example, ethyl 4-piperidinecarboxylate. Another name for ethyl 4-piperidinecarboxylate is ethyl isonidepecotate. The reaction of step (a) is carried out at a temperature in the range of, for example, 0 to 45 ° C, conveniently in the range from 1 5 to 35 ° C, more conveniently in the range from 25 to 30 ° C. The (C 1 -C 6) alkyl-4-piperidinecarboxylate compounds of Formula 11 and the di-tert-butyl dicarbonate starting material used in step (a) of the process are commercially available or can be prepared using convenal methods. For example, the compounds of (C1-C6) alkyl-4-piperidinecarboxylate of the Formula II can be prepared as described in the Japanese patent application number JP 0302162 A2. The ter-butnaol that is formed in step (a) is a by-product of the reaction between the (C 1 -C 6) alkyl-4-piperidinecarboxylate compound of Formula I 1 and di-tert-butyl dicarbonate. In the process of the present invention, this by-product is substantially conveniently and easily removed from the reaction mixture, for example, by distillation in step (b).

It is advantageous to substantially remove the ter-butanol by-product from the reaction mixture, for example, by distillation in step (b) because any by-product of tert-butanol that is not removed is likely to react with the product. reducing agent in step (c), thereby reducing the amount of reducing agent available for the desired reaction with the compound of Formula IV. Thus, the removal of the ter-butanol by-product in step (b) allows the correct stoichiometry of the reactants in step (c) of the process and, therefore, a more efficient reaction in that step. This in turn provides a high yield and purity of the compound of Formula V in step (c). By the term "substantially removed", we mean that at least 85% of the ter-butanol by-product that is formed in step (a) is removed, for example, by distillation. Normally, the distillation is conducted until an internal temperature in the range between 102 to 1 12 ° C is reached. The distillation in step (b) is conveniently conducted either at atmospheric or partially reduced pressure The reducing agents suitable for use in step (c) include sodium bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride and hydride diisobutylaluminum, more particularly, the reducing agent used in step (c) in sodium bis (2-methoxyethoxy) aluminum hydride The step reaction (c) is carried out at a temperature in the range, for example, from 20 to 55 ° C, conveniently in the range from 30 to 50 ° C, more conveniently in the range from 35 to 45 ° C. As the skilled person would appreciate, the step reaction (c) usually provides the reduction of sub- products in addition to the desired compound of Formula V. The by-products of reduction include alcohol by-products.The alcohol by-products originate from the -O- (C 1 -C 6) alkyl portion of the ester group in the compound of Formula I V and can also originate from the reducing agent. For example, when the compound of Formula IV is 4- (1-tert-butoxycarbonyl) pyperidine) ethyl carboxylate and the reducing agent used in step (c) is bis (2-methoxyethoxy) aluminum hydride. of sodium, normal reduction by-products include aluminum salts and alcohol by-products, such as, ethanol and 2-methoxyethanol. The alcohol by-products are substantially easily and conveniently removed from the reaction mixture for example by distillation in step (d). It is advantageous to substantially remove the alcohol by-products in step (d) because such by-products that are not removed will probably react with the sulfonating agent in step (e), thereby creating impurities that could contaminate the desired product and reducing the amount of sulfonating agent available for the desired reaction with the compound of Formula V. In this way, the removal of the alcohol by-products allows the correct stoichiometry of the reagents in step (e) of the process and, therefore, a more efficient reaction in that step. This in turn provides a high yield and purity of the compound of Formula I I in step (e). By the term "substantially removed" we mean that at least 98% of the by-products of alcohol that are formed in step (c) are removed, for example, by distillation. Normally, the distillation is conducted until an internal temperature in the range from 102 ° C to 1 12 ° C is reached. The distillation in step (d) is conveniently conducted either at atmospheric or partially reduced pressure. The distillation in step (d) also substantially removes any water that is present in a normal manner. This again allows the correct stoichiometry of the reagents in step (e) of the process because any water that is not removed will probably react with the sulfonating agent in step (e), thereby reducing the amount of the sulfonating agent available for the desired reaction with the compound of Formula V. By the term "substantially removed" we mean that less than 20 mol% of water remains after distillation. How the expert will appreciate it, it is usually necessary to quench the reaction mixture in step (c) to remove any unreacted reducing agent that is present before the reaction in step (e) is conducted. Normally, the extinction step also removes some of the reduction by-products listed above, for example, aluminum salts and some, but not all, alcohol by-products. Suitable extinguishing agents can in general be chosen from any agent that is described in the literature and / or known to the skilled person. For example, when the reducing agent used in step (c) is sodium bis (2-methoxyethoxy) aluminum hydride, the extinguishing agent can usually be an aqueous solution of potassium sodium tartrate (also known as sodium salt). Rochelle). Normally, the resulting aqueous phase (containing the extinguished reducing agent) is then removed by separation. The extinguishing step is conducted before the distillation in step (d). A suitable base to be used in step (e) is a tertiary amine base, for example, triethylene diamine. The step reaction (e) is carried out at a temperature in the range, for example, from 1 5 to 45 ° C, more conveniently in the range from 25 to 35 ° C. As the skilled person will appreciate, it is usually necessary to extinguish the reaction mixture in step (e) to remove any unreacted sulfonating agent that is present. Suitable extinguishing agents can be chosen in general from any agent that is described in the literature and / or known to the skilled person. For example, a suitable extinguishing agent may be a base, such as, sodium hydroxide or potassium carbonate. In one aspect, the process for the manufacture of a compound of Formula I I may further include step (f) of isolating and / or purifying the compound of Formula I I. Step (f) may comprise any step or suitable procedure for isolating the desired product which is described in the literature and / or which is known to the skilled person. The particular steps that would be of use would provide product of high quality and high purity. For example, step (f) may comprise the steps of washing the compound of Formula I I with water and / or aqueous citric acid. Step (f) may, for example, also comprise crystallization using a suitable solvent system. An example of a suitable solvent system is a solvent system comprising toluene and isohexane, which provides a compound of Formula II in a high purity, usually in a purity of more than 98%, conveniently greater than 99.5% and in a high yield , normally in a yield greater than 80%, conveniently greater than 85%. As an expert will appreciate, step (f) may also comprise the temperature cycling step (also referred to as "Ostwald maturation") the compound of Formula II, in order to improve the physical form of the product, if it is necessary. Another key intermediate that can be used in the preparation of ZD6474 is a protected derivative of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, the compound of Formula VI: VI wherein R1 is an acid-labile protecting group, such as, benzyl, substituted benzyl, tert-butyl, allyl or methoxyethoxymethyl. Example 2 of WO 01/32651 and Example 24 of WO 97/32856 each describe a route for the preparation of a hydrochloride salt of a compound of Formula VI, wherein R is benzyl. The route involves the reaction of a 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride salt with 4-bromo-2-fluoroaniline in a 2-propanol solvent to provide the hydrochloride salt of the compound of Formula VI, which is isolated. It is stated in Example 2 of WO 01/32651 that the hydrochloride salt of 7-benzyloxy-4-chloro-6-methoxyquinazoline is prepared according to Example 1 of WO 97/22596. In Example 1 of WO 97/22596, the hydrochloride salt of 7-benzyloxy-4-chloro-6-methoxyquinazine is prepared by the reaction of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one with Thionyl chloride in a N, N-dimethylformamide solvent. The same process for the preparation of the hydrochloride salt of 7-benzyloxy-4-chloro-6-methoxyquinazoline is described in Example 4 of WO 97/32856. WO 98/1 0767 describes a route for the preparation of 6,7-disubstituted 4-anilinoquinazolin compounds. The route involves the reaction of a 6,7-disubstituted quinazolinone compound with a chlorinating agent and a catalyst in the absence of a solvent or with a chlorinating agent in the presence of a trap agent to provide a 4-chloroquinazoline compound 6, 7-disubstituted. The 6,7-disubstituted 4-chloroquinazoline compound is then reacted with a substituted aniline compound, optionally in the presence of a suitable base, to provide a hydrochloride salt of the 6,7-disubstitute 4-anilinoquinazoline compound, the which can then be converted to the free base. There is no disclosure in WO 98/10767 of 7-benzyloxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline or of a process for its preparation. The routes described in the prior art documents for the preparation of a compound of Formula Vi are satisfactory for the synthesis of relatively small amounts of the compound. However, all require the isolation and / or purification of intermediates. This results in a satisfactory, but not high overall performance of the compound of Formula VI. Therefore, there is a need for a more efficient synthesis of a compound of Formula VI to be used to make larger amounts of that compound. Preferably, the new synthesis should not involve expensive and slow isolation and / or purification procedures. In this way, the new synthesis should reduce the number of isolation and / or purification procedures, thereby reducing costs and manufacturing time. The new synthesis should also allow effective isolation of the compound of Formula VI in a crystalline form in high purity and yield, said crystalline form should have good filtration characteristics. According to a second aspect of the present invention, a process for the manufacture of a compound of Formula VI is provided: SAW wherein R1 is an acid-labile protecting group; of a compound of the Formula Vi l: vu said process comprises the steps of: (g) reacting the compound of the Formula VI with a suitable chlorinating agent in the presence of a suitable base and a suitable solvent, wherein the reaction is carried out at: (g-1) adding a mixture of the compound of the Formula VI and the base in the solvent to a mixture of the chlorinating agent in the solvent at a temperature in the range from 60 to 1 10 ° C, conveniently 60 to 80 ° C over a period of about 60 minutes; or (g-2) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at room temperature over a period of about 15 minutes and then heating the reaction mixture over a period of about 90 minutes to a temperature in the range from 70 to 90 ° C and stirring the reaction mixture at that temperature for about 1 hour; or (g-3) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at a temperature in the range from 60 to 1 1 0 ° C, conveniently 70 to 90 ° C over a period of about 15 minutes, to form a compound of Formula VI II: VIII; Y (h) reacting the compound of Formula VI I I with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form a hydrochloride salt of the compound of Formula VI; and subsequently the compound of Formula VI obtained in the form of the hydrochloride salt can be converted to the free base or in the form of an alternative salt, if necessary. The term "acid labile protecting group" refers to groups which are easily removed under acidic conditions. Suitable methods for protection are those known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (for illustration see T. W. Green, Protectíve Groups in Organic Synthesis (Protective Groups in Organic Synthesis), John Wiley and Sons, 1991). Protective groups suitable for R1 include benzyl, substituted benzyl (eg, 4-alkoxybenzyl and C1-4alkylbenzyl), tert-butyl, 1,1-dimethyl-1-ethylmethoyl, allyl, substituted allyl (such as C1). -4-alkylalkyl) or methoxyethoxymethyl. In another embodiment, R1 is benzyl. The process of the second aspect of the invention is advantageous because it allows a compound of Formula VI to be made in high purity and high yield on a larger scale. Normally, each of the steps of the process of the second aspect of the present invention proceeds in more than 90% yield. A suitable solvent for step (g) is selected from an aryl alkyl ether, such as anisole, a dialkyl ether, such as 1,2-dimethyl ether, a substituted halobenzene, such as, chlorobenzene or trifluorotoluene or a substituted alkylbenzene , such as, xylene, ethyl benzene or toluene. In one embodiment of the invention, the solvent for step (g) is anisole or toluene. In another embodiment of the invention, the solvent for step (g) is toluene. Steps (g) and (h) are both conducted in the same solvent, said solvent is selected from a suitable solvent as described above. This allows the process to be conducted as a continuous process without isolation and / or purification of the intermediate compound of Formula VI I I. This significantly reduces the time and cost of manufacturing the compound of Formula VI on a larger scale. Additionally, the use of a single solvent can allow recycling of the solvent, which increases the efficiency of the process and provides environmental benefits. The use of toluene or anisole as the reaction solvent is advantageous because these solvents minimize the formation of by-products that can be derived by dimerization of the compound of Formula Vi, as discussed above. The choice of solvent also allows easy and convenient isolation of the compound of Formula VI. For example, when the reaction mixture is cooled to room temperature, the compound of Formula VI normally forms a solid, said solid can then be collected by any conventional method. The mode of addition of the reagents in step (g) (ie, as described in steps (g-1), (g-2) and (g-3)) is advantageous because it minimizes the formation of sub-products / impurities in that step. Normally, any such by-products / impurities are predominantly formed by dimmerization of the compound of Formula Vi 1. Reducing the formation of by-products / impurities allows the intermediate compound of Formula VI I I produced in step (g) to be used in step (h) without isolation and / or purification. Reducing the formation of by-products / impurities in step (g) also allows the correct stoichiometry of the reagents in step (h) of the process and, therefore, a more efficient reaction in that step. This in turn provides a high yield and high purity of the compound of Formula VI in step (h). In one aspect of the invention, steps (g) and (h) are both conducted in toluene as the solvent. In another aspect of the invention, steps (g) and (h) are both conducted in anisole as the solvent. In still another aspect of the invention, steps (g) and (h) are conducted in a solvent mixture of toluene and anisole. A suitable chlorinating agent to be used in step (g) is phosphorus oxychloride. Typically, in step (g), a molar excess of chlorinating agent is used in relation to the compound of Formula VII. For example, a molar excess in the range from 1.3 to 2.0, conveniently in the range from 1.7 to 1.8, can be used. A suitable base to be used in step (g) is a selected base of triethylamine and N, N-diisopropylethylamine. In particular, the base is N, N-diisopropylethylamine. The use of N, N-diisopropylethylamine as the base in step (g) is advantageous because it minimizes the formation of by-products that can be derived by dimerization of the compound of Formula Vi, as discussed above (e.g. as compared to the use of triethylamine as the base in step (g)). Addition of a chloride source to the reaction mixture (such as, for example, triethylamine hydrochloride) can also reduce the formation of such by-products. In step (g-1), the reaction is carried out at a temperature in the range from 60 to 1110 ° C, conveniently 60 to 80 ° C, conveniently in the range from 65 to 80 ° C, more conveniently in the range from 70 to 75 ° C. In step (g-2), the addition of reagents is performed at room temperature. By the term "room temperature" we mean a temperature in the range from 1 0 to 30 ° C, especially a temperature in the range from 1 5 to 25 ° C, more especially a temperature of approximately 20 ° C. The reaction mixture is then heated to a temperature in the range from 70 to 90 ° C, conveniently in the range from 75 to 85 ° C, more conveniently in the range from 80 to 85 ° C. In step (g-3), the reaction is carried out at a temperature in the range from 60 to 1110 ° C, conveniently 70 to 90 ° C, conveniently in the range from 75 to 85 ° C, more conveniently in the range from 80 to 85 ° C. In step (g), the term "from about" is used in the expressions "about 60 minutes", "about 1 5 minutes", "about 90 minutes" and "about 1 hour" to indicate that the The aforementioned periods should not be interpreted as absolute values because, as will be appreciated by those skilled in the art, the periods may vary slightly. For example, the aforementioned periods may vary by ± 50%, in particular by ± 1 5%, in particular by ± 10%, of the values quoted in step (g). As the skilled person will appreciate, in step (g), the mixture of the compound of the Formula Vi 1 and the base in a suitable solvent will normally take the form of a suspension. The mixture of the chlorinating agent in a solvent selected from toluene and anisole will normally take the form of a solution. However, a variety of factors can cause these forms to vary. Such factors may include, for example, the amount of each of the reagents added to the solvent, the particular base or chlorinating agent selected for use in step (g) and / or the temperature selected for use in step (g) - The reaction of step (h) is carried out at a temperature in the range from 60 to 85 ° C, conveniently in the range from 65 to 80 ° C, more conveniently in the range of 70 to 75 ° C. In one aspect of the invention, following step (h) of the process, the compound of Formula VI is used directly in another process (e.g., in a process for making 7-hydroxy-4- (4-bromo-2- fluoroanilino) -6-methoxyquinazoline as discussed below). In another aspect of the invention, following step (h) of the process, the compound of Formula VI is isolated and / or purified, for example, before storage, handling and / or further reaction. Thus, in one aspect of the invention, the process for manufacturing a compound of Formula VI further includes step (i) of isolating the compound of Formula VI. Step (i) may comprise any step or suitable procedure for isolating the desired product which is described in the literature and / or which is known to the skilled person. The particular steps that would be of use would provide product of high quality and high purity. The reaction mixture can be cooled to room temperature, to which the compound of Formula VI normally forms a solid, and the solid thus formed can be collected by any conventional method, for example, by filtration. Both the compound of the Formula Vi 1 and the starting material of 4-bromo-2-fluoroaniline are commercially available or can be prepared using conventional methods. For example, the compound of Formula Vi 1, wherein R is benzyl, can be prepared as described in Example 2 below, preparation of starting materials. Another key intermediate that can be used in the preparation of ZD6474 is 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, the compound of Formula IX: IX Example 2 of WO 01/32651 and Example 24 of WO 97/32856 each describe a route for the preparation of a hydrochloride salt of a compound of Formula IX. The route involves the reaction of a hydrochloride salt of 7-benzyloxy-4- (4-bromo-2-fluoroanilino) -6-methoxy-quinazoline with trifluoroacetic acid to provide the compound of Formula IX. As discussed above, WO 98/10767 describes a route for the preparation of 6,7-disubstituted 4-anilinoquinazoline compounds. There is no disclosure in WO 98/10767 of 6-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline or of a process for its preparation.

The routes described in the prior art documents for the preparation of a compound of Formula IX are satisfactory for the synthesis of relatively small amounts of the compound. However, all require the isolation and / or purification of intermediates. This results in a satisfactory, but not high overall performance of the compound of Formula IX. Therefore, there is a need for a more efficient synthesis of the compound of Formula IX suitable for use to make larger amounts of that compound. Preferably, the new synthesis should not involve expensive and slow purification procedures. In this way, the new synthesis should reduce the number of isolation and / or purification procedures required, thereby reducing costs and manufacturing time. Preferably, the new synthesis should minimize the number of solvents used throughout the process, which improves environmental performance and provides the opportunity for solvent recovery. The new synthesis should also allow effective crystallization of the compound of Formula IX in a crystalline form with good filtration characteristics and in high purity and yield. According to a third aspect of the present invention, there is provided a process for the manufacture of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, a compound of Formula IX: IX of a compound of the Formula Vi l: VII said process comprises the steps of: (g) reacting the compound of the Formula VI with a suitable chlorinating agent in the presence of a suitable base and a suitable solvent, wherein the reaction is carried out at: (g-1) adding a mixture of the compound of the Formula VI and the base in the solvent to a mixture of the chlorinating agent in the solvent at a temperature in the range from 60 to 1 10 ° C, conveniently 60 to 80 ° C over a period of about 60 minutes; or (g-2) adding the chlorinating agent to a mixture of the compound of the Formula VII and the base in the solvent at room temperature over a period of about 15 minutes and then heating the reaction mixture over a period of about 90 minutes at a temperature in the range from 70 to 90 ° C and stirring the reaction mixture at that temperature for about 1 hour; or (g-3) adding the chlorinating agent to a mixture of the compound of the Formula VII and the base in the solvent at a temperature in the range from 60 to 1 1 0 ° C, conveniently 70 to 90 ° C over a period of about 15 minutes, to form a compound of Formula VIII: VIII; (h) reacting the compound of Formula VIII with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form a hydrochloride salt of the compound of Formula VI; SAW; Y and subsequently the compound of the Formula IX obtained in the free base form can be converted to a salt form and the compound of the Formula IX obtained in the form of a salt can be converted into the free base or in the form of an alternative salt , if required. The process of the third aspect of the invention is advantageous because it allows the compound of Formula IX to be made in high purity and high yield on a larger scale. Normally, each of the steps of the process of the third aspect of the present invention proceeds in at least 95% yield. Usually, the process of the third aspect of the present invention produces the compound of Formula IX in at least 85% yield. Steps (g), (h) and (j) are all conducted in the same solvent, said solvent is selected from an aryl alkyl ether, such as anisole, a dialkyl ether, such as 1,2-dimethyl ether, a benzene substituted halo, such as chlorobenzene or trifluorotoluene or an alkyl substituted benzene, such as xylene, ethylbenzene or toluene. In one embodiment of the invention, the solvent for step (g), (h) and (j) is anisole or toluene. In another embodiment of the invention, the solvent for step (g), (h) and (j) is toluene. This allows the process to be conducted as a continuous process without isolation and / or purification of the intermediate compounds of Formulas VI I I and VI. This significantly reduces the time and cost of manufacturing the compound of Formula IX on a larger scale. The use of a single solvent can allow recycling of solvent, which increases the efficiency of the process and provides environmental benefits. The use of these solvents as the reaction solvent is advantageous because these solvents minimize the formation of by-products that can be derived by dimerization of the compound of Formula VII, as discussed above. The choice of solvent may also allow easy and convenient isolation of the compound of Formula VI. For example, when the reaction mixture is cooled to room temperature, the compound of Formula VI normally forms a solid, which can then be collected by any conventional method. As discussed above, the mode of addition of the reagents in step (g) (ie, as described in steps (g-1), (g-2) and (g-3)) is advantageous due to which minimizes the formation of by-products / impurities in that step (said by-products / impurities are usually formed predominantly by the dimerization of the compound of Formula Vi). This allows the intermediate compound of Formula VIII produced in step (g) to be used in step (h) without isolation and / or purification. Reducing the formation of by-products / impurities in step (g) allows the correct stoichiometry of the reagents in step (h) of the process and, therefore, a more efficient reaction in that step. This in turn provides a high yield and high purity of the compound of Formula VI in step (h).

In one aspect of the invention, steps (g), (h) and (j) are all conducted in toluene as the solvent. The use of toluene as the solvent in step (j), wherein R1 is benzyl is vetanus because the toluene acts to capture the benzyl cation that is generated during the deprotection reaction. This helps reduce the benzylated impurities that can potentially be formed in step (j) of the process. Toluene also provides a stronger crystallization of compound IX and a crystalline form of compound IX with superior filtration characteristics. In another aspect of the invention, steps (g), (h) and (j) are all conducted in a single solvent, such as anisole, chlorobenzene, trifluorotoluene, xylene or ethylbenzene. A suitable chlorinating agent to be used in step (g) is phosphorus oxychloride. Normally, in step (g), a molar excess of chlorinating agent is used in relation to the compound of Formula VII. For example, a molar excess in the range from 1.3 to 2.0, conveniently in the range from 1.7 to 1.8, can be used. A suitable base to be used in step (g) is a base selected from triethylamine, tripropylamine and N, N-diisopropylethylamine. In particular, the base is triethylamine. The use of triethylamine as the base in step (g) is advantageous since it allows a stronger crystallization of compound IX and a crystalline form of compound IX with superior filtration characteristics. In step (g-1), the reaction is carried out at a temperature in the range from 60 to 1100 ° C, conveniently 60 to 80 ° C, conveniently in the range from 65 to 75 ° C, more conveniently in the range from 70 to 75 ° C. In step (g-2), the addition of reagents is performed at room temperature. By the term "room temperature", we mean a temperature in the range from 1 0 to 30 ° C, especially a temperature in the range from 15 to 25 ° C, more especially a temperature of approximately 20 ° C. The reaction mixture is then heated to a temperature in the range from 70 to 90 ° C, conveniently in the range from 75 to 85 ° C, more conveniently in the range from 80 to 85 ° C. In step (g-3), the reaction is carried out at a temperature in the range from 60 to 1110 ° C, conveniently 70 to 90 ° C, conveniently in the range from 75 to 85 ° C, more conveniently in the range from 80 to 85 ° C.

In step (g), the term "from about" is used in the expressions "approximately 60 minutes", "approximately 15 minutes", "approximately 90 minutes" and "approximately 1 hour" to indicate that the aforementioned periods they should not be interpreted as absolute values because, as will be appreciated by those skilled in the art, the periods may vary slightly.For example, the aforementioned periods may vary by ± 50%, in particular ± 15%, in particular by ± 1 0 % of the values quoted in step (g) As will be appreciated by the skilled person, in step (g), mixing the compound of Formula Vi and the base in a suitable solvent will normally take the form of a suspension. of the chlorinating agent in a selected solvent of toluene and anisole will usually take the form of a solution, however, a variety of factors can cause these forms to vary, such factors may include, for example, the amount of each of the reagents added to the solvent and the particular base or chlorinating agent selected for use in step (g). The step reaction (h) is carried out at a temperature in the range from 60 to 90 ° C, conveniently 60 to 85 ° C, conveniently in the range from 65 to 80 ° C, more conveniently in the range from 70 to 75 °. C. In this aspect of the invention, following the manufacture of the compound of Formula VI in step (h), the compound is used directly in step (j) to make a compound of Formula IX. In other words, the compound of Formula VI is not isolated as such, but is used as a solution or paste in a solvent selected from an aryl alkyl ether, such as anisole, a dialkyl ether, such as, 1,2-dimethoxyethanol, a substituted halobenzene, such as chlorobenzene or trifluorotoluene or a benzene alkyl substituted, such as, xylene, ethyl benzene or toluene. In one embodiment of the invention, the solvent for step (j) is anisole or toluene. In another embodiment of the invention, the solvent for step (j) is toluene. Therefore, the compound of Formula IX can be manufactured from a compound of Formula VI in a process of a kettle. A suitable method for removing the acid-labile protecting group in situ in step (j) is by reaction with an acid, such as trifluoroacetic acid. Optionally a second acid (such as, hydrogen chloride or hydrogen bromide) may be used in addition to, or as a replacement for, the trifluoroacetic acid. When an acid is used to remove R in step (j), then the compound of Formula IX is obtained in the form of a salt. The use of trifluoroacetic acid in step (j) is advantageous because it allows easy isolation of the compound of Formula IX, for example, by crystallization of trifluoroacetic acid by the addition of water and cooling or by addition of an aqueous base of alkali metal, such as potassium hydroxide, sodium hydroxide, sodium acetate, potassium acetate, more preferably potassium hydroxide followed by water and cooling. The crystalline solid thus formed can be collected by any conventional method, for example, by filtration.

The reaction of step (j) is carried out at an emperature in the range from 60 to 90 ° C, conveniently 60 to 80 ° C, more conveniently in the range from 70 to 75 ° C. In one aspect of the invention, following step (j) of the process, the compound of formula IX is isolated and / or purified. Any suitable step or procedure for isolating and / or purifying the desired product that is described in the literature and / or known to the skilled person, can be used. The particular steps that would be of use would provide product of high quality and high purity. For example, the compound of Formula IX can be isolated from trifluoroacetic acid by the addition of water and cooling or more preferably by the addition of an aqueous base of alkali metal, such as potassium hydroxide and water and cooling as discussed above. . According to a fourth aspect of the present invention, there is provided a process for the manufacture of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, a compound of Formula IX: IX of a compound of the Formula VI: said process comprises the steps of: (g) reacting the compound of the Formula VII with a suitable chlorinating agent in the presence of a suitable base and a suitable solvent, wherein the reaction is carried out al: (g-1) add a mixture of the compound of the formula Vi and the base in the solvent to a mixture of the chlorinating agent in the solvent at a temperature in the range from 60 to 1 10 ° C, conveniently 60 to 80 ° C over a period of approximately 60 minutes; or (g-2) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at room temperature over a period of about 15 minutes and then heating the reaction mixture over a period of about 90 minutes to a temperature in the range from 70 to 90 ° C and stirring the reaction mixture at that temperature for about 1 hour; or (g-3) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at a temperature in the range from 60 to 1 1 0 ° C, conveniently 70 to 90 ° C over a period of about 15 minutes, to form a compound of Formula VI II: (h) reacting the compound of Formula VIII with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form a hydrochloride salt of the compound of Formula VI: SAW; (i) isolating the compound of Formula IV; and (k) removing R1 from the compound of Formula VI to form the compound of Formula IX or a salt thereof; and subsequently the compound of the Formula IX obtained in the free base form can be converted to a salt form and the compound of the Formula IX obtained in the form of a salt can be converted into the free base or in the form of an alternative salt , if required. The process of the fourth aspect of the invention is advantageous because it allows the compound of Formula IX to be made in high purity and high yield on a larger scale. Steps (g) and (h) are both conducted in the same solvent, said solvent is selected from an aryl alkyl ether, such as anisole, a dialkyl ether, such as, 1,2-dimethyl ether, a substituted halobenzene, such as chlorobenzene or trifluorotoluene or an alkyl substituted benzene, such as xylene, ethyl benzene or toluene. In one embodiment of the invention, the solvent for step (g) and (h) is anisole or toluene. In another embodiment of the invention, the solvent for step (g) and (h) is toluene. This allows the process to be conducted as a continuous process without isolation and / or purification of the intermediate compound of Formula VI I I. This significantly reduces the time and cost of manufacturing the compound of Formula IX on a larger scale. The use of a single solvent in steps (g) and (h) can allow the recycling of solvent, which increases the efficiency of the process and provides environmental benefits. The use of toluene or anisole as the reaction solvent in steps (g) and (h) is advantageous because these solvents minimize the formation of by-products that can be derived by dimerization of the compound of Formula VII., as discussed earlier. The choice of solvent also allows easy and convenient isolation of the compound of Formula VI. For example, when the reaction mixture is cooled to room temperature, the compound of Formula VI normally forms a solid, said solid can then be collected by any conventional method. As discussed above, the mode of addition of the reagents in step (g) (ie, as described in steps (g-1), (g-2) and (g-3)) is advantageous due to which minimizes the formation of by-products / impurities in that step (said by-products / impurities are usually formed predominantly by dimerization of the compound of Formula Vi 1). This allows the intermediate compound of Formula VI I I produced in step (g) to be used in step (h) without isolation and / or purification. Reducing the formation of by-products / impurities in step (g) allows the correct stoichiometry of the reagents in step (h) of the process and, therefore, a more efficient reaction in that step. This in turn provides a high yield and purity of the compound of Formula VI in step (h). In one aspect of the invention, steps (g) and (h) are both conducted in toluene as the solvent. In another aspect of the invention, steps (g) and (h) are both conducted in anisole as the solvent. A suitable chlorinating agent to be used in step (g) is phosphorus oxychloride. Typically, in step (g), a molar excess of chlorinating agent is used in relation to the compound of Formula VII.

For example, a molar excess in the range from 1.3 to 2.0, conveniently in the range from 1.7 to 1.8, can be used. A suitable base to be used in step (g) is a selected base of triethyl amine and N, N-diisopropylethylamine. In one embodiment, the base is triethylamine. The use of triethylamine as the base in step (g) is advantageous because it allows a stronger crystallization of compound IX and a crystalline form of compound IX with superior filtration characteristics. In another embodiment, the base is N, N-diisopropylethylamine. The use of NN-diisopropylethylamine as the base in step (g) is advantageous because it minimizes the formation of by-products that can be derived by dimerization of the compound of Formula Vi 1, as discussed above (eg, as compared to the use of triethylamine as the base in step (g)). Addition of a chloride source to the reaction mixture (such as, for example, triethylamine hydrochloride) can also reduce the formation of such by-products). In step (g-1), the reaction is carried out at a temperature in the range from 60 to 1100 ° C, conveniently 60 to 80 ° C, conveniently in the range from 65 to 75 ° C, more conveniently in the range from 70 to 75 ° C. In step (g-2), the addition of reagents is performed at room temperature. By the term "room temperature", we mean a temperature in the range from 1 0 to 30 ° C, especially a temperature in the range from 1 5 to 25 ° C, more especially a temperature of about 20 ° C. The reaction mixture is then heated to a temperature in the range from 70 to 90 ° C, conveniently in the range from 75 to 85 ° C, more conveniently in the range from 80 to 85 ° C. In step (g-3), the reaction is carried out at a temperature in the range from 60 to 1110 ° C, conveniently 70 to 90 ° C, conveniently in the range from 75 to 85 ° C, more conveniently in the range from 80 to 85 ° C.

In step (g), the term "from about" is used in the expressions "about 60 minutes", "about 1 5 minutes", "about 90 minutes" and "about 1 hour" to indicate that the The aforementioned periods should not be interpreted as absolute values because, as will be appreciated by those skilled in the art, the periods may vary slightly. For example, the aforementioned periods may vary by ± 50%, in particular by ± 1 5%, in particular by ± 10%, of the values quoted in step (g). As will be appreciated by the skilled person, in step (g), the mixture of the compound of the Formula Vi 1 and the base in a suitable solvent will normally take the form of a suspension. The mixture of the chlorinating agent in a solvent selected from toluene and anisole will normally take the form of a solution. However, a variety of factors can cause these forms to vary. Such factors may include, for example, the amount of each of the reagents added to the solvent and the particular base or chlorinating agent selected for use in step (g). The reaction of step (h) is carried out at a temperature in the range from 60 to 90 ° C, conveniently 60 to 90 ° C, conveniently in the range from 65 to 80 ° C, more conveniently in the range from 70 to 75 °. C. In this aspect of the invention, following the manufacture of the compound of Formula VI in step (h), the compound is isolated and, optionally, purified in step (i) of the process. The isolated compound of Formula VI is then used in step (k) to make a compound of Formula IX, either immediately or by storage for an appropriate period. The isolation of the compound of Formula VI in step (i), wherein R 1 is benzyl is advantageous because it allows a more extensive choice of methods for removing the benzyl group of the compound of Formula VI in step (k), for example, compared to when this step is conducted in situ. Step (k) where R1 is benzyl, can comprise any step or suitable procedure to remove the benzyl group that is described in the literature and / or that is known to the skilled person. The particular steps that would be of use would provide product of high quality and high purity. For example, in step (k), the benzyl group can be removed by reaction with a suitable hydrogenation agent, such as palladium on carbon, for example, in the presence of a suitable moderating agent, such as zinc bromide or zinc iodide. The use of a hydrogenation agent is advantageous because it provides a highly efficient method of removing the benzyl group in step (k) and because it allows the efficient removal of by-products from the waste stream. A further suitable method for removing the acid labile protecting group, wherein R is a benzyl group in step (k) is by reaction with an acid, such as trifluoroacetic acid. Optionally, a second acid (such as, hydrogen chloride or hydrogen bromide) may be used in addition to, or as a replacement for, trifluoroacetic acid. When an acid is used to remove the benzyl group in step (k), then the compound of Formula IX is obtained in the form of a salt. The use of trifluoroacetic acid in step (k) is advantageous because it allows easy isolation of the compound of Formula IX, for example, by crystallization of trifluoroacetic acid by addition of water and cooling or more preferably by the addition of a base. aqueous alkali metal, such as, potassium hydroxide, sodium hydroxide, sodium acetate, potassium acetate, more preferably potassium hydroxide, water-quenched and cooling. The crystalline solid thus formed can be collected by any conventional method, for example, by filtration. The reaction of step (k), wherein R is benzyl, can be carried out at any temperature and in any solvent suitable for the particular method of removal of the benzyl group being used. Examples of suitable solvents for acid-based removal of the benzyl group include ethanol, an aryl alkyl ether, such as anisole, a dialkyl ether, such as, 1,2-dimethyl ether, a substituted halobenzene, such as, chlorobenzene or trifluorotoluene or an alkyl substituted benzene, such as xylene, ethyl benzene or toluene or dichloromethane. In one aspect of the invention, following step (k) of the process, the compound of Formula IX is isolated and / or purified. Any suitable step or procedure for isolating and / or purifying the desired product that are described in the literature and / or known to the skilled person can be used. The particular steps that would be of use would provide product of high quality and high purity. Another key intermediate that can be used in the preparation of ZD6474 is 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-ethoxy-qinazoline, the compound of the Formula X: X Example 2 of WO 01/32651 describes a e for the preparation of a compound of Formula X. The e involves the reaction of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyqinazoline with carbonate of potassium and 1- (tert-butoxycarbonyl) -4- (4-methylphenylsulfonyloxymethyl) piperidine in a N, N-dimethylformamide solvent to provide the compound of Formula X. As discussed above, WO 98/10767 describes a e for the preparation of 6,7-disubstituted 4-anilinoquinazoline compounds. There is no disclosure in WO 98/1 0767 of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline or of a process for its preparation . The es described in the prior art documents for the preparation of a compound of Formula X are satisfactory for the synthesis of relatively small amounts of the compound. However, there is a need for a more efficient synthesis of the compound of Formula X suitable for use to make larger amounts of that compound. Preferably, the new synthesis should not involve expensive and slow purification procedures. In this way, the new synthesis should reduce the number of isolation and / or purification procedures required, thereby reducing costs and manufacturing time. Preferably, the new synthesis should minimize the number of solvents used thhout the process, which improves environmental performance and provides the opportunity for solvent recovery. The new synthesis should also provide the compound of Formula X in a high purity and in a high yield. According to a fifth aspect of the present invention, a process for the manufacture of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilin) -6 is provided. -methyloxyazoline, a compound of the Formula X: X from a compound of the Formula Vi l: VII said process comprises the steps of converting the compound of the Formula VII to a compound of the Formula IX: IX when conducting a process as discussed above in relation to the third or fourth aspect of the invention; and (I) reacting the compound of Formula IX with a compound of Formula I I as defined above in the presence of a suitable base to provide a compound of Formula X or a salt thereof; and subsequently the compound of Formula X obtained in the form of the free base in either solvated or unsolvated forms, can be converted to a salt form and the compound of Formula X obtained in the form of a salt can be converted into the salt. free base or in the form of an alternative salt, if necessary. The process of the fifth aspect of the invention is advantageous because it allows the compound of Formula X to be made in high purity and high yield on a larger scale. Normally, the process of the fifth aspect of the present invention proceeds in more than 80% yield. The process of the fifth aspect of the invention is also advantageous for at least the reasons discussed above in relation to the third and fourth aspects of the invention. Typically, the compound of Formula IX is isolated and / or purified before step (I) is conducted, for example, using any step or suitable procedure that is described in the literature and / or is known to the skilled person. as discussed before. In another embodiment of the invention, following the manufacture of the compound of Formula IX in step (j), wherein R 1 is benzyl (or substituted benzyl) and when hydrogenation is used as the deprotection method of the benzyl g, the compound is used directly in step (I) to make a compound of Formula X. In other words, the compound of Formula IX is not isolated as such, but is used as a solution or paste in a suitable solvent, such as N -methyl pyrrolidone, dimethylformamide or dimethylacetamide. In one embodiment of the invention, the solvent for step (j) is N-methylpyrrolidone. Therefore, the compound of Formula X can be manufactured from a compound of Formula VI I I in a process of a kettle. A suitable base to be used in step (I) is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium tert-butanol and potassium hydroxide.

Step (1) can be conducted in any suitable solvent and at any suitable temperature. When the base used in step (I) is selected from sodium carbonate and potassium carbonate, suitable solvents include, for example, N-methylpyrrolidone, N-ethylpyrrolidone, dimethylacetamide, dimethyl sulfoxide, sulfoline, methyl ethyl ketone and N, Nd. methylformamide. In this aspect, the step (I) can normally be conducted at a temperature in the range from 60 to 120 ° C, conveniently 70 to 105 ° C, conveniently in the range from 80 to 1 00 ° C, conveniently in the range of 70-90 ° C, conveniently in the range from 90 to 95 ° C. In an additional mode in the range of 75-85 ° C. When the base used in step (I) is selected from sodium hydroxide and potassium hydroxide, suitable solvents include, for example, an aryl alkyl ether, such as anisole, a dialkyl ether, such as, 1, 2-dimethoxyethane , a substituted halobenzene, such as chlorobenzene or trifluorotoluene or an alkyl substituted benzene, such as xylene, ethylbenzene or toluene or acetonitrile. In one embodiment of the invention, the solvent for step (I) is anisole or toluene. In another embodiment of the invention, the solvent for step (I) is toluene. In this aspect, the step (I) can normally be conducted at a temperature in the range from 60 to 90 ° C, conveniently in the range from 65 to 85 ° C, conveniently in the range from 70 to 80 ° C. In this aspect, step (I) can be conveniently conducted by adding water, the base (such as sodium hydroxide or potassium hydroxide) and a suitable phase transfer catalyst in toluene to the reaction mixture. Suitable phase transfer catalysts include, for example, tetrabutylammonium bromide and Adogen® 464 (methyltrialkyl (C8-10) ammonium chloride, CAS 63393-96-4). In one aspect, the process of the fifth aspect of the invention can include step (m) of isolating the compound of Formula X. Step (m) can comprise any step or process suitable for isolating the compound of Formula X which is described in the literature and / or known to the skilled person. For example, when the base used in step (I) is selected from sodium carbonate and potassium carbonate, step (m) may comprise the steps of: (m-1) adding water and allowing the crystallization of the compound to occur of Formula X, collecting the compound of Formula X and washing the compound of Formula X with water, followed by a solvent selected from ethyl acetate, butyl acetate and acetonitrile at a temperature in the range from 25 to 55 ° C; or (m-2) adding water and an alcohol selected from methanol, ethanol, isopropanol and n-propanol and allowing the crystallization of the compound of Formula X to occur, collecting the compound of Formula X and washing the compound of Formula X with a mixture of water and the alcohol selected from methanol, ethanol, isopropanol and n-propanol, followed by a solvent selected from ethyl acetate, butyl acetate and acetonitrile at a temperature in the range from 25 to 55 ° C, conveniently from 45 to 55 ° C. The steps (m-1) and (m-2) are advantageous because they are efficient to remove the unreacted compound of Formula IX, as well as the impurities that are formed routinely during step (I) of the process. Such impurities include those formed by reaction of the compound of Formula I I at the nitrogen atom of position 1 on the quinazoline ring instead of at the desired position on the hydroxy substituent. When the base used in step (I) is selected from sodium hydroxide and potassium hydroxide, step (m) may comprise the steps of allowing the crystallization of the compound of Formula X to take place (For example, to crystallize from of the toluene phase) and collecting the compound of the Formula X by any conventional method. This aspect is advantageous because the compound of formula X crystallizes directly from the reaction mixture in high yield (e.g., at least 80% yield) and in high quality without the need to further purify the product. In steps (m), the compound of Formula X thus formed (for example, which is isolated as a crystalline solid) can be collected by any conventional method, for example, by filtration. The crystalline solid collected can then be, if necessary, washed with the appropriate solvent and then dried. According to a sixth aspect of the present invention, a process for the manufacture of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6 is provided. -methoxyquinazoline, a compound of the Formula X: X from 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, a compound of Formula IX: IX (I) reacting the compound of Formula IX with a compound of Formula II as defined above, in the presence of a suitable base to provide a compound of Formula X or a salt thereof; and (m) isolating the compound of Formula X by: (m-1) adding water and allowing the crystallization of the compound of Formula X to occur, collecting the compound of Formula X and washing the compound of Formula X with water , followed by a solvent selected from ethyl acetate, butyl acetate and acetonitrile at a temperature in the range from 25 to 55 ° C; conveniently 45 to 55 ° C; or (m-2) adding water and an alcohol selected from methanol, ethanol, isopropanol and n-propanol (in particular isopropanol) and allowing the crystallization of the compound of Formula X to occur, collecting the compound of Formula X and washing the compound of Formula X with a mixture of water and the alcohol selected from methanol, ethanol, isopropanol and n-propanol, followed by a solvent selected from ethyl acetate, butyl acetate and acetonitrile at a temperature in the range from 25 to 55 ° C, conveniently 25 to 55 ° C; and subsequently the compound of Formula X obtained in the form of the free base in either solvated or unsolvated forms (or solvent solvate of NMP, ethyl acetate or a mixture of both), can be converted into a salt form, and the compound of Formula X obtained in the form of a salt can be converted to the free base or to the form of an alternative salt, if necessary. The process of the sixth aspect of the invention is advantageous because it allows the compound of Formula X to be made in high purity and high performance on a larger scale. Normally, each of the steps of the process of the sixth aspect of the present invention proceeds in more than 80% yield. The process provides efficient removal of any unreacted compound of Formula IX, as well as any impurities that are routinely formed during step (I) of the process. Such impurities include those formed by the reaction of the compound of Formula I I at the nitrogen atom of position 1 in the quinazoline ring instead of the desired position in the hydroxy substituent. A suitable base to be used in step (I) is selected from sodium carbonate, sodium hydroxide, potassium hydroxide and potassium carbonate. Step (I) can be conducted in any suitable solvent or at any suitable temperature. When the base used in step (I) is selected from sodium carbonate and potassium carbonate, suitable solvents include, for example, N-methylpyrrolidone, N-ethylpyrrolidone and N, N-dimethylformamide. In this aspect, the step (I) can normally be conducted at a temperature in the range from 70 to 1 05 ° C, conveniently from 80 to 1 00 ° C, conveniently from 90 to 95 ° C. Steps (m-1) and (m-2) are advantageous because they are efficient to remove the unreacted compound of Formula IX, as well as impurities that are formed routinely during step (I) of the process. Such impurities include those formed by reacting the compound of Formula I I at the nitrogen atom of position 1 on the quinazoline ring instead of at the desired position on the hydroxy substituent. In steps (m-1) and (m-2), the crystalline solid thus formed can be collected by any conventional method, for example, by filtration. The crystalline solid collected can, if necessary, be washed then with the appropriate solvent and then dried. The compound of Formula I I used in step (I) of the processes of the fifth and sixth aspects of the invention can be obtained by any conventional literature or method. In one aspect of the invention, the compound of Formula II used in step (I) of the fifth or sixth aspect of the invention, is prepared according to the process of the first aspect of the invention, as discussed above. According to a seventh aspect of the invention, a process for the manufacture of ZD6474 is provided: ZD6474 from a compound of Formula X: X said process comprises the steps of: (n) reacting the compound of formula X with formic acid and formaldehyde or a formaldehyde polymer, conveniently in water at a temperature in the range from 70 to 95 ° C, conveniently 70 up to 90 ° C to form a formic acid salt of ZD6474; (o) adding an inert organic solvent selected from tetrahydrofuran, butyronitrile and methanol and a suitable base in order to form the free base of ZD6474; subsequently the ZD6474 obtained in the free base form can be converted to a pharmaceutically acceptable salt, if necessary. In step (n) of the process of the seventh aspect of the invention, the reaction proceeds via a transient intermediate, said intermediate is 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (piperidin-4-ylmethoxy) quinazole, a compound of Formula XI: XI The process of the seventh aspect of the invention is advantageous because it allows ZD7464 to be made in high purity and high yield on a larger scale. Normally, each of the steps of the process of the seventh aspect of the present invention proceeds in more than 90% yield. The compound of Formula X used in step (n) of the process of the seventh aspect of the invention can be obtained by any conventional literature or method (for example, as described in WO 01/32651 discussed previously). Alternatively, in one aspect of the invention, the compound of Formula X used in step (n) of the seventh aspect of the invention is prepared according to the process of the fifth or sixth aspect of the invention, as discussed above . The passage (n) is conducted at a temperature in the range from 70 to 95 ° C, conveniently 70 to 90 ° C, conveniently in the range from 75 to 85 ° C, more conveniently at about 80 ° C. Preferably, step (n) is conducted under an inert atmosphere, for example, under a nitrogen atmosphere. This is advantageous because the step (n) process can produce hydrogen gas and carbon monoxide as a by-product, said hydrogen gas must be removed from the reaction vessel in a safe and effective manner. In step (n), the formic acid salt of ZD7474 is produced. This salt is converted to the free base of ZD7464 in step (o) of the process. In step (n) examples of formaldehyde polymers include paraformaldehyde and s-trioxane (1, 3, 5 trioxane). An inert organic solvent suitable for use in step (o) is selected from tetrahydrofuran, butyronitrile and methanol (in particular tetrahydrofuran or methanol). The inert organic solvent is added to the reaction mixture after the completion of the reaction in step (n). As will be appreciated by the skilled person, it may be necessary to cool the reaction mixture before the inert organic solvent is added. A suitable base to be used in step (o) is sodium hydroxide or potassium hydroxide (in particular potassium hydroxide). The addition of a base in step (o) converts the formic acid salt of ZD6474 to the free base of ZD6474. When the inert organic solvent used in step (o) is selected from tetrahydrofuran and butyronitrile, the product ZD6474 is effectively transferred from the aqueous phase to the organic phase. This is because, once made, the free base of ZD6474 is preferentially soluble in the organic solvent (while the formic acid salt of ZD6474 is slube in the aqueous phase). When the inert organic solvent used in step (o) is methanol, the free base of ZD6474 normally crystallizes directly from the reaction mixture. When the base is potassium hydroxide, it is particularly advantageous if the format salt is completely soluble in the methanol solvent and does not contaminate the isolated compound ZD6474. It also provides a crystalline compound with good filtration characteristics. (This can be isolated as either the anhydrous form, a methanoate form or a mixed methanoate hydrate). Thus, the step (o) of the process is advantageous because it helps and simplifies the isolation and purification of the product ZD6474, in particular when the process is conducted on a larger scale. The step (o) is conducted at a temperature in the range from 30 to 70 ° C, conveniently in the range from 40 to 65 ° C, more conveniently in the range from 40 to 60 ° C. In one aspect, the process of the seventh aspect of the invention may include step (p) of isolating and / or purifying the free base of ZD6474. Step (p) may comprise any step or process suitable for isolating and / or purifying the free base of ZD6474 which is described in the literature and / or known to the skilled person. Alternatively, for example, when the inert organic solvent used in step (o) is selected from tetrahydrofuran and butyronitrile, step (p) may comprise the steps of: (p-1) separating and removing the aqueous phase from the organic phase; (p-2) charge n-butyl acetate to the organic phase; (p-3) washing the organic phase with water and separating and removing the aqueous phase from the organic phase; (p-4) adding tetrahydrofuran and n-butyl acetate to the organic phase; (p-5) distilling the organic phase in order to substantially remove water and tetrahydrofuran and provide a suspension of ZD6474 in predominantly n-butyl acetate; (p-6) allow the crystallization of the ZD6474 to finish; and (p-7) collect the ZD6474. Steps (p-1), (p-2) and (p-3) are advantageous because they easily and simply remove the salts of formic acid and residual formaldehyde or formaldehyde polymer from the product ZD6474 dissolved in the organic phase. In one aspect, the steps (p-1), (p-2), (p-3) and (p-4) are each conducted at a temperature in the range from 50 to 65 ° C, conveniently in the range from 55 to 65 ° C, more conveniently of about 60 ° C. Normally, steps (p-1), (p-2) and (p-3) can be repeated each twice before step (p-4) is conducted. Step (p-5) removes substantially any water and tetrahydrofuran that is present in the organic phase that has been separated from the aqueous phase in steps (p-1) and (p-3). The distillation is conducted in order to provide a solvent composition containing about 90% w / w n-butyl acetate. In other words, the solution of ZD6474 in predominantly n-butyl acetate is a solution of ZD6474 in a solvent composition containing about 90% w / w n-butyl acetate. Normally, the distillation is conducted until an internal temperature in the range from 90 to 1 1 0 ° C, conveniently 90 up to 104 ° C is suitably set in the range from 100-1 1 0 ° C. The distillation in step (p-5) is conveniently conducted at atmospheric pressure (or reduced pressure but more conveniently at ambient pressure).

So that there is no doubt in (p-6), where it refers to "allow the crystallization of ZD6474 to finish", it means that the crystallization process has finished under the conditions used, does not mean that 100% of ZD6474 in the mixture of reaction has crystallized. An alternative step (p) of isolating and / or purifying the free base of ZD6474, when the inert organic solvent used in step (o) is tetrahydrofuran, can comprise the steps of: (p-8) adding water to the solution of ZD6474 in the organic phase obtained after step (p-1) with the to allow the crystallization of ZD6474 to occur; and (p-9) collect the ZD6474. In each of the above isolation steps, the crystalline solid thus formed can be collected by any conventional method, for example, by filtration. The crystalline solid collected can, if necessary, be further purified, and then dried. The step (p) of isolating the product ZD6474 is advantageous because it provides ZD7464 in a high yield (for example, normally in more than 90% yield) and a high purity (for example, usually in more than 99% purity). ). In addition, step (p) provides a form of ZD6474 that is easily filterable on a larger scale. In another aspect of the present invention, ZD6474 prepared according to the process of the seventh aspect of the invention as discussed above, can be further purified. The further purification of ZD6474 may comprise any step or suitable procedure for isolating and / or purifying ZD6474 which is described in the literature and / or known to the skilled person. Alternatively, the further purification of ZD6474 may comprise the steps of heating a suspension of ZD6474 as prepared in the process of the seventh aspect of the present invention in a mixture of tetrahydrofuran, water and butyl acetate at reflux, cooling the resulting mixture at a temperature in the range from 50 to 65 ° C (conveniently about 60 ° C), separating the aqueous and organic phases and filtering the organic phase. The filtrate can then be combined with additional tetrahydrofuran and butyl acetate and the resulting mixture heated to a temperature in the range of 90 to 1 10 ° C, conveniently 90 to 1 1 0 ° C (conveniently in a range from 1 00 to 1 10 ° C) before cooling to a temperature in the range from 40 to -10 ° C, conveniently 25 to 0 ° C (conveniently in the range from 0 to 10 ° C, more conveniently of about 5 ° C, in a additional at a temperature of approximately 25 ° C) to provide a paste of ZD6474. The ZD6474 can then be harvested by any conventional method, for example, by filtration and optionally washed with ethyl acetate. This is advantageous because the process described reduces the level of water at the end of the distillation to below 1%, thus ensuring that the anhydrous form of ZD6474 is produced. Alternatively, for example, when the inert organic solvent used in step (o) is tetrahydrofuran, step (p) may comprise the steps of: (p-1) separating and removing the aqueous phase from the organic phase; (p-2) filter the organic phase; (p-3) loading n-butyl acetate to the organic phase; (p-4) washing the organic phase with water and separating and removing the aqueous phase from the organic phase; (p-5) adding tetrahydrofuran and n-butyl acetate to the organic phase; (p-6) distilling the organic phase in order to substantially remove water and tetrahydrofuran and provide a suspension of ZD6474 in predominantly n-butyl acetate; (p-7) cooling and charging additional tetrahydrofuran; and (p-8) allow the crystallization of the ZD6474 to finish; and (p-9) collect the ZD6474. The step (p-7) is advantageous because it improves the quality of the product obtained by solubilizing the impurities in the mother liquors. This allows telescoping the production of API (active pharmaceutical ingredient) raw with the isolation of the API purified in a single step. According to an eighth aspect of the present invention, there is provided a process for the manufacture of ZD6474 of a compound of the Formula VI: Vü said process comprises the steps of: (g) reacting the compound of the Formula VII with a suitable chlorinating agent in the presence of a suitable base and a solvent selected from chlorobenzene, trifluorotoluene, xylene, ethylbenzene, toluene and anisole, more specifically anisole and toluene, wherein the reaction is performed at: (g-1) adding a mixture of the compound of the Formula VII and the base in the solvent to a mixture of the chlorinating agent in the solvent at a temperature in the range from 60 to 90 ° C, conveniently 60 to 80 ° C over a period of about 60 minutes; or (g-2) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at room temperature over a period of about 15 minutes and then heating the reaction mixture over a period of about 90 minutes to a temperature in the range from 70 to 90 ° C and stirring the reaction mixture at that temperature for about 1 hour; or (g-3) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at a temperature in the range from 60 to 1 1 0 ° C, conveniently 70 to 90 ° C over a period of about 15 minutes, to form a compound of Formula VI II: VIII; (h) reacting the compound of Formula VI I I with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form a compound of Formula VI: VI (j) removing R1 of the compound of Formula VI in situ in the presence of the solvent used in steps (g) and (h) to form the compound of Formula IX: IX (I) reacting the compound of Formula IX with a compound of Formula I I as defined above in the presence of a suitable base to provide a compound of Formula X; X (n) reacting the compound of formula X with formic acid and formaldehyde or a formaldehyde polymer conveniently in water at a temperature in the range of 70 to 90 ° C to form the formic acid salt of ZD6474; and (o) adding an inert organic solvent selected from tetrahydrofuran, butyronitrile and methanol and a suitable base, in order to form the free base of ZD6474; and optionally (p) further purifying ZD6474 in a mixture of tetrahydrofuran, water and butyl acetate to provide a required crystalline anhydrous form suitable for the manufacture of tablets; Subsequently ZD6474 obtained in the free base form can be converted into a pharmaceutically acceptable salt form, if necessary. The process of the eighth aspect of the invention is advantageous in that it allows ZD6474 to be made in high purity and high performance on a larger scale. Normally, each of the steps of the process of the seventh aspect of the present invention proceeds in more than 90% yield. The preferred aspects of the process of the eighth aspect of the invention are as set forth above in relation to individual steps as described in the first, second, third, fourth, fifth, sixth and seventh aspects of the present invention. In particular, the preferred aspects of the process of the eighth aspect of the invention are as set forth above, for example, in relation to individual steps of the third, fifth, sixth and / or seventh aspects of the present invention.

Conveniently, steps (g), (h) and (j) of the process of the eighth aspect of the present invention are all conducted in toluene as the solvent and triethylamine as the base. Conveniently, a suitable method for removing the benzyl group in situ in step (j) of the process of the eighth aspect of the present invention, wherein R is benzyl, is by reaction with trifluoroacetic acid. Conveniently, the base used in step (I) of the process of the eighth aspect of the present invention is potassium carbonate and the suitable solvent is N-methylpyrrolidone. The process of the eighth aspect of the present invention can typically include the step (m) of isolating the compound from the Formula X before steps (n) and (o) are conducted.

Conveniently, step (m) can be conducted as described hereinabove.

Conveniently, a suitable base to be used in step (o) of the eighth aspect of the present invention is potassium hydroxide. Conveniently, a solvent suitable for use in step (o) of the eighth aspect of the present invention is methanol. The process of the eighth aspect of the present invention may include step (p) of isolating and / or purifying the free base of ZD6474. Step (p) may be conducted as described hereinabove. The invention is illustrated below by means of the following non-limiting Examples and Data in which, unless stated otherwise: (i) the evaporations were carried out by rotary vacuum evaporation and working procedures were carried out after the removal of residual solids, such as, drying agents by filtration; (ii) the returns are given for illustration only and are not necessarily the maximum attainable; (ii) the melting points are not corrected and were determined using a Mettler DSC820e; (V) the structures of the final products were confirmed by nuclear magnetic resonance (usually protons) (NMR) and mass spectral techniques; Proton magnetic resonance chemical shift values were measured on the delta scale and the peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet; who, quintet; all samples were run on a Bruker DPX 400 MHz at 300K in the indicated solvent, 16 scans, pulse repetition time 10 seconds; (v) the intermediates were not fully characterized in a general manner and the purity was assessed by NMR analysis; (vi) chemical symbols have their usual meanings; SI units and symbols are used; and (vii) the following abbreviations have been used: THF tetrahydrofuran I PA isopropanol DMSO dimethylsulfoxide TEDA triethylenediamine DI PEA N, N-diisopropylethylamine TFA trifluoroacetic acid NMP N-methylpyrrolidinone DMF N, N-dimethylformamide DMA N, N-dimethylacetamide v / v ratio volume / volume w / w weight / weight ratio w / v weight / volume ratio EXAMPLES EXAMPLE 1 Preparation of 1- (tert-butoxycarbonyl) -4- (4-methylphenylsulfonyloxymethyl) -piperidine (the compound of Formula II) Di-tert-butyl dicarbonate (88.63 g) in toluene (296 ml) was added to a stirred solution of ethyl isonipecotate (62.88 g) in toluene (317 ml). The reaction mixture was then distilled at atmospheric pressure, stirring apimately 1 30 ml of distillate, with a final distillation temperature of 12 ° C. Sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al, 65% w / w solution in toluene, 161 g) in toluene (220 ml) was then added to the reaction mixture over a period of about 60 minutes. A 0.5 molar Rochelle salt solution (191 ml) was added to the reaction mixture and the aqueous phase was separated at 40 ° C. The organic phase was washed with 1% w / v brine (3 x 1 36 ml) and with water (36 ml). The solution was distilled at atmospheric temperature, stirring apimately 400 ml of distillate, with a final distillation temperature of 12 ° C. Triethylenediamine (51.62 g) was added to the reaction mixture followed by tosyl chloride (87.90 g) in toluene (41.6 ml) over a period of about 60 minutes. Sodium hydroxide (2N, 160 ml) was added to the reaction mixture and the organic layer was separated and washed successively with water (80 ml), citric acid (0.5M, 80 ml) and water (80 ml). The organic phase was concentrated under reduced pressure with a maximum internal temperature of 70 ° C, collecting apimately 600 ml of distillate. The solution was cooled to 20 ° C and isohexane (1 60 ml) was added. Once the crystallization had occurred, additional isohexane (320 ml) was added. The uct was placed in temperature cycles at 40 ° C, the suspension was cooled to 5 ° C and the uct was isolated by filtration and dried at 40 ° C. Yield: 127.9 g, 86.5%; NMR spectrum (CDCU) 1 .0-1 .2 (m, 2H). 1.45 (s, 9H), 1.65 (d, 2H), 1.75-1.9 (m, 2H), 2.45 (s, 3H), 2.55-2J5 (m, 2H) 3.85 (d, 1 H), 4.0-4.2 (br s, 2H), 7.35 (d, 2H), 7.8 (d, 2H); Mass spectrum [ESI]: (MNa) + = 392.

EXAMPLE 2 Preparation of the 7-benzyloxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline hydrochloride salt (the hydrochloride salt of the compound of Formula VI) 7-benzyloxy-6 was mixed methoxy-3,4-dihydroquinazol-n-4-one (20.00 g) with anisole (190 ml) and N, N-düsoylethylamine (1.74 g). The reaction mixture was made inert with nitrogen and cooled to 1 5 ° C. Phosphorus oxychloride (14.1 2 g) was charged to the reaction mixture over a period of 15 minutes, followed by anisole (10 ml) as a wash. The reaction mixture was stirred for 1 5 minutes at 1 5 ° C and then heated to 80 ° C over a period of 90 minutes. The reaction mixture was then stirred at 80 ° C for one hour. A solution of 4-bromo-2-fluoroaniline (16.8 g) in anisole (20 ml) was added to the reaction mixture over a period of 40 minutes. The reaction mixture was stirred at 80 ° C for 90 minutes. The reaction mixture was then cooled to 25 ° C and the uct was isolated by filtration. Yield: 26.9 g, 84%; NMR spectrum (DMSOd6, CD3COOD) 4.0 (s, 3H), 5.37 (s, 2H), 7.35-7.5 (m, 4H), 7.52-7.62 (m, 4H), 7.8 (d, 1 H), 8.14 ( s, 1 H), 8.79 (s, 1 H); Mass spectrum fESH (M + H) + = 454.0591. The starting material 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one was prepared as follows: A mixture of vanillic acid (200 g), acetonitrile (600 ml) and N-ethyldiisoylamine (580 ml) was heated to reflux. Then benzyl bromide (347 ml) was added over a period of 3 hours. The reaction mixture was refluxed for 1.5 hours. Triethylamine (50 ml) was added and the reaction mixture was refluxed for an additional 30 minutes. Acetonitrile (400 ml) was added and the reaction mixture was heated to 81 ° C. Water (300 ml) was added and the reaction mixture was cooled to 45 ° C. The reaction mixture was maintained at 45 ° C for 30 minutes until crystallization occurred. The reaction mixture was then allowed to cool to 24 ° C and then further cooled to 8 ° C and the uct (benzyl 4- (benzyloxy) -3-methoxybenzoate) was isolated by filtration. The solid was washed with water (3 x 500 ml) and then dried under vacuum at 45 ° C. Yield: 387 g, 93.4%; NMR spectrum (CDCI3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 6.9 (d, 1 H), 7.2-7.4 (m, 10H), 7.6-7J (m, 2H); Mass spectrum (M + H) + = 349.2. Benzyl 4- (benzyloxy) -3-methoxybenzoate (78 g) was mixed with dichloromethane (580 ml), water (72 ml) and glacial acetic acid (288 ml). The mixture was cooled to 1 0 ° C. Concentrated sulfuric acid (108 ml) was added in a controlled manner maintaining the temperature of the reaction mixture low at 25 ° C. Concentrated nitric acid (17.5 ml) was then added maintaining the temperature of the reaction mixture below 20 ° C. The reaction mixture was then stirred at 20 ° C for 23 hours. The lower aqueous layer was removed and the organic layer was washed with water (290 ml). The organic layer was separated and distilled at 270 ml at atmospheric pressure. Isopropanol (750 ml) was added to the reaction mixture at 45 ° C. The reaction mixture was then heated to 40 ° C and stirred at this temperature for 15 minutes. The resulting suspension was then cooled to 20 ° C, then to 5 ° C and kept at this temperature for one hour. The product (benzyl 4-benzyloxy) -5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (200 ml) and dried at less than 25 ° C. Yield: 78.4 g, 89.6%; NMR spectrum (CDCI3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 7.1 (s, 1 H), 7.3-7.4 (m, 1 0H), 7.5 (s, 1 H); Mass spectrum (M + HT = 394.1, benzyl 4- (benzyloxy) -5-methoxy-2-n-benzoate (77 g) was dissolved in acetonitrile (882 ml), sodium dithionite (160.5 g) was added to The solution and the temperature were adjusted to 25 ° C. Water (588 ml) was then added, maintaining the temperature at 25 ° C. The pH was maintained at 6 using 8.8 M sodium hydroxide during the reduction, the paste was then heated at 65 ° C and the lower aqueous phase was removed, concentrated hydrochloric acid (35% w / w, 7.25 ml) was then added, the pulp was allowed to cool to 40 ° C and then to 20 ° C. of sodium hydroxide (47% w / w, 2.4 ml) and the pulp was cooled to 0 ° C. The product (benzyl 2-amino-4- (benzyloxy) -5-methoxybenzoate) was isolated by filtration, washed with water (2 x 1 96 ml) and then dried at 40 ° C under vacuum Yield: 66.2 g, 92.4%; NMR spectrum (CDCI3) 3.8 (s, 3H), 5.1 (s, 2H), 5.3 (s, 2H), 6.2 (s, 1 H), 7.3-7.4 (m, 10H); Mass spectrum (M + H) * = 364.1. Benzyl 2-amino-4- (benzyloxy) -5-methoxybenzoate (5.55 kg), formamidine acetate (2.2 kg) and isobutanol (33.3 I) were mixed. The reaction mixture was then heated to 97 ° C and stirred at this temperature for 6 hours. The reaction mixture was then cooled to 25 ° C over a period of at least one hour and then stirred at this temperature for 30 minutes. The product (7-benzyloxy-6-methoxy-3,4-dihydro-quinazolin-4-one) was isolated by filtration, washed with isobutanol (6.1 I) and dried in the vacuum oven at a temperature of 40 to 45 °. C. Yield: 4.25 kg, 98%; NMR spectrum (DMSOd6) 3.9 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1 H), 7.3-7.5 (m, 6H), 8.0 (s, 1 H); Mass spectrum (M + HT = 283.1. The starting material 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one was further prepared as follows: A mixture of vanillic acid (20 g), acetonitrile (60 g) ml) and N-ethyldiisopropylamine (58 ml) was heated to reflux, then benzyl bromide (34.7 ml) was added within 15 minutes.The reaction mixture was refluxed for about 10 hours, triethylamine (5 ml) was added. ) and the reaction mixture was refluxed for an additional 30 minutes Acetonitrile (40 ml) and water (30 ml) were added and the reaction mixture was cooled to 45 ° C. The reaction mixture was maintained at 45 ° C. C until crystallization occurred, then the reaction mixture was allowed to cool to 24 ° C and then further cooled to 8 ° C and the product (benzyl 4- (benzyloxy) -3-methoxybenzoate) was isolated by The solid was washed with water (3 x 50 ml) and then dried under vacuum at 45 ° C. Product: 38.7 g, 93%; NMR spectrum (CDCI3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 6.9 (d, 1 H), 7.2-7.4 (m, 10H), 7.6-7.7 (m, 2H); Mass spectrum (M + H) + = 349.2. Benzyl 4- (benzyloxy) -3-methoxybenzoate (135 g) was dissolved in dichloromethane (339 ml). Ice-cold acetic acid (1 75.5 g) was added and the mixture was cooled to 10 ° C. Concentrated sulfuric acid (151.6 g) was added in a controlled manner keeping the temperature of the reaction mixture below 25 ° C. Concentrated nitric acid (61.6 g) was then added in 15 minutes keeping the temperature of the reaction mixture below 25 ° C. The reaction mixture was then added at 40 ° C and stirred for 3 hours. The lower aqueous layer was removed and the organic layer was washed twice with water (2 x 168 ml). The organic layer was distilled at atmospheric pressure to remove dichloromethane (186 ml). Isopropanol (339 ml) was added to the reaction mixture at 40 ° C. The reaction mixture was maintained at 40 ° C for 15 minutes. The resulting suspension was then cooled to 20 ° C within 30 minutes, then at 5 ° C and kept at this temperature for one hour. The product (benzyl 4- (benzyloxy) -5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (336 ml) and dried at less than 25 ° C. Yield: 135J g, 89.6%; NMR spectrum (CDCI3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 7.1 (s, 1 H), 7.3-7.4 (m, 10H), 7.5 (s, 1 H) ); Mass spectrum (M + H) + = 394.1. Benzyl 4- (benzyloxy) -5-methoxy-2-nitrobenzoate (90 g) was charged to acetonitrile (660 g). 85% sodium dithionite (75 g) was added to the solution and the temperature was adjusted to 20 ° C. Then water (516 g) was added, maintaining the temperature at 20 ° C. The pulp was heated to 65 ° C and stirred for 30 minutes. Sodium dithionite (75 g) was added and the mixture was stirred for another 30 minutes. The lower aqueous phase was removed. Then concentrated hydrochloric acid (33% w / w, 12.48 g) was added to adjust to a pH of < 1 . The suspension is maintained for 1 hour. The paste was cooled to 20 ° C over 30 minutes. The sodium hydroxide solution (20% w / w, 59.29 g) was added to give a pH of 10. The pulp was cooled to 0 ° C and stirred for one hour. The product (benzyl 2-amino-4- (benzyloxy) -5-methoxybenzoate) was isolated by filtration, washed twice with water (2 x 222 ml) and then dried at 60 ° C under vacuum. Yield: 78.81 g, 95%; NMR spectrum (CDCU) 3.8 (s, 3H), 5.1 (s, 2H), 5.3 (s, 2H), 6.2 (s, 1 H), 7.3-7.4 (m, 10H); Mass spectrum (M + H) + = 364.1. Benzyl 2-amino-4- (benzyloxy) -5-methoxybenzoate (80.0 g), formamidine acetate (32.0 g) and isobutanol (480 ml) were mixed. The reaction mixture was then heated to 97 ° C and stirred at this temperature for 6 hours. The reaction mixture was then cooled to 25 ° C over a period of at least one hour and then stirred at this temperature for 30 minutes. The product (7-benzyloxy-6-methoxy-3,4-dihydroquinnazolin-4-one) was isolated by filtration, washed with isobutanol (64.2 g) and dried in the vacuum oven at a temperature of 40 to 45. ° C. Yield: 60.8 g, 98%; NMR spectrum (DMSOd6) 3.9 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1 H), 7.3-7.5 (m, 6H), 8.0 (s, 1 H); Mass spectrum (M + H) * = 283.1.

EXAMPLE 3 Preparation of the 7-benzyloxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline hydrochloride salt (the hydrochloride salt of the compound of Formula VI) 7-Benzyloxy-6-methoxy- 3,4-dihydroquinazolin-4-one (20.00 g) with toluene (190 ml) and N, N-diisoproylethylamine (1.74 g). The reaction mixture was made inert with nitrogen and cooled to 15 ° C. Phosphorus oxychloride (19.8 g) was charged to the reaction mixture over a period of 15 minutes, followed by toluene (10 ml) as a wash. The reaction mixture was stirred for 1 5 minutes at 1 5 ° C and then heated to 80 ° C over a period of 90 minutes. The reaction mixture was then stirred at 80 ° C for two hours. A solution of 4-bromo-2-fluoroaniline (16.8 g) in toluene (40 ml) was added to the reaction mixture over a period of 40 minutes, followed by toluene (10 ml) as a wash. The reaction mixture was then stirred at 80 ° C for 4 hours. The reaction mixture was then cooled to 25 ° C and the product was isolated by filtration. The filter cake was washed twice with water (2 x 40 ml). Yield: 34.37 g, 87%; NMR spectrum (DMSOd6, CD3COOD) 4.0 (s, 3H), 5.37 (s, 2H), 7.35-7.5 (m, 4H), 7.52-7.62 (m, 4H), 7.8 (d, 1 H), 8.14 ( s, 1 H), 8.79 (s, 1 H); Mass spectrum [ESI] (M + H) + = 454.0591.

EXAMPLE 4 Preparation of the trifluoroacetic acid salt of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (the trifluoroacetic acid salt of the compound of the Formula IX) 7-benzyloxy-6-methoxy- 3,4-Dihydroquinazolin-4-one (100 g), triethylamine (59.3 ml) and toluene (650 ml) were charged to a vessel and made inert with nitrogen. The contents were heated to 40 ° C and charged over a period of about 40 minutes to a solution of phosphorus oxychloride (97J g) in toluene (400 ml) maintained at 73 ° C in a vessel which was made inert with nitrogen. The reaction mixture was then maintained at a temperature of about 73 ° C for a period of about 90 minutes. 4-Bromo-2-fluoroaniline (84.1 g) was dissolved in toluene (250 ml) and charged to the reaction mixture at 73 ° C and kept stirring at this temperature for about 4 hours. Trifluoroacetic acid (350 ml) was then added to the reaction mixture at 73 ° C and the reaction mixture was stirred at 73 ° C for 6 hours and then cooled to 60 ° C. Water (1750 ml) was added to the reaction mixture and the temperature was maintained at 60 ° C for about 30 minutes and then heated to 70 ° C and stirred at 70 ° C for about 22 hours. The reaction mixture was then cooled to 20 ° C and the product isolated by filtration, washed with water (200 ml) and dried at 50 ° C. Yield: 1 20 g, 93%; Spectrum of N MR (DMSOd6) 4.0 (s, 3H), 7.24 (s, 1 H), 7.56 (m, 2H), 7.78 (d, 1 H), 8.02 (s, 1 H), 8.73 (s, 1 H); Mass spectrum (M + H) + = 454.0591.

EXAMPLE 5 Preparation of the trifluoroacetic acid salt of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (the trifluoroacetic acid salt of the compound of Formula IX) 7-benzyloxy-6 was charged methoxy-3,4-dihydroquinazolin-4-one (15 g), triethylamine (9.0 ml) and toluene (90 ml) were added to a vessel and made inert with nitrogen. The contents were kept at room temperature and charged over a period of about 40 minutes to a solution of phosphorus oxychloride (14.7 g) in toluene (60 ml) maintained at 73 ° C in a vessel which was made inert with nitrogen. This was followed by a toluene line wash (7.5 ml). The reaction mixture was then maintained at a temperature of about 73 ° C for a period of about 90 minutes. 4-Bromo-2-fluoroaniline (1 2.6 g) was dissolved in toluene (30 ml) and charged to the reaction mixture at 73 ° C and kept stirring at this temperature for about 4 hours. Then trifluoroacetic acid (60 ml) was added to the reaction mixture at 73 ° C and the reaction mixture was stirred at 73 ° C for 6 hours and then cooled to 60 ° C. Potassium hydroxide was charged (48-50% w / w, 6.1 ml) in water (0.5 ml) about 30 minutes followed by one hour maintained at 60 ° C. Water (1 80 ml) was added to the reaction mixture in about 70 minutes, followed by trifluoroacetic acid salt seed of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (0.13 g) . The batch was maintained at 60 ° C for approximately 60 minutes and then water (60 ml) was added in about 20 minutes. The reaction mixture was maintained for about two hours, then cooled to 20 ° C and the product was isolated by filtration, washed with toluene (50 ml) and methanol / water (1: 1, 50 ml) and dried at 50 ° C. Yield: 22 g, 89%; NMR spectrum (DMSOd.) 4.0 (s, 3H), 7.24 (s, 1 H), 7.56 (m, 2H), 7J8 (d, 1 H), 8.02 (s, 1 H), 8J3 (s, 1 H); Mass spectrum (M + H) + = 454.0591.

EXAMPLE 6 Preparation of a hydrogen chloride salt of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxy-quinazoline (the hydrogen chloride salt of the compound of Formula IX) 7-benzyloxy-6- methoxy-3,4-dihydroquinazolin-4-one (30.00 g) was mixed with triethylamine hydrochloride (2.99 g), anisole (285 ml) and N, N-diisoproylethylamine (20.71 g) The reaction mixture was made inert with nitrogen and cooled to 1 5 ° C. Phosphorus oxychloride (21.4 g) was added to the reaction mixture over a period of 15 minutes, followed by an anisole wash (30 ml). then for 15 minutes at 15 ° C and then it was heated at 80 ° C over a period of 90 minutes.The reaction mixture was stirred at 80 ° C for one hour.A solution of 4-bromo-2-fluoroaniline (25.2 g. ) in anisole (1.5 ml) was added to the reaction mixture over a period of 25 minutes The reaction mixture was stirred for 4 hours at 80 ° C. Hydrogen chloride was charged aqueous (35% w / w, 122 ml) and acetic acid (198 ml) to the reaction mixture. The reaction mixture was stirred for 3 hours and then the anisole layer was removed. The reaction mixture was cooled to 25 ° C and the solid was isolated by filtration. Yield: 13.9 g, 54%; NMR spectrum (DMSOdfi) 4.0 (s, 3H). 7.43 (s, 1 H), 7.5 (m, 2H), 7.7 (d, 1 H), 8.37 (s, 1 H), 8.72 (s, 1 H); Mass spectrum (M + H) * = 454.0591.

EXAMPLE 7 Preparation of the hydrogen chloride salt of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (the hydrogen chloride salt of the compound of Formula IX) Phosphorus oxychloride was added ( 6.0 ml) over a period of 60 minutes to a stirred paste of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (10.0 g) and N, N-diisopropylethalamine (7.45 ml) in toluene (1 05). ml) at 20 ° C. After stirring the reaction mixture for 30 minutes at 20 ° C, the reaction mixture was heated over a period of 90 minutes at 73 ° C and then stirred for an additional 3 hours at that temperature. 4-Bromo-2-fluoroaniline (8.4 g) in toluene (20 I) was added to the reaction mixture at 73 ° C, followed by a toluene wash (5 ml). Trifluoroacetic acid (35 ml, 3.5 vol) was added over a period of 10 minutes to the reaction mixture at 73 ° C and the reaction mixture was stirred at that temperature for 5 hours. The reaction mixture was then cooled to 60 ° C and water (175 ml) was added over a period of 15 minutes. The reaction mixture was heated to 68 ° C and stirred at this temperature for 8 hours. The reaction mixture was heated to 68 ° C and stirred at that temperature for 8 hours. The reaction mixture was then cooled to 20 ° C over a period of 1 hour and the product was filtered and washed with water (20 ml). Yield: 1 1 .56 g, 90%; NMR spectrum (DMSOd6) 4.0 (s, 3H), 7.43 (s, 1 H), 7.5 (m, 2H), 7.7 (d, 1 H), 8.37 (s, 1 H), 8J2 (s, 1 H) ); Mass spectrum (M + H) * = 454.0591.

EXAMPLE 8 Preparation of the trifluoroacetic acid salt of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (the trifluoroacetic acid salt of the compound of Formula IX) Phosphorus oxychloride (6.0 ml) was added ) over a period of 15 minutes to a stirred paste of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (10.0 g) and triethylamine (5.9 ml) in toluene (105 ml) at 73 ° C and the reaction mixture was stirred for an additional 3 hours. 4-Bromo-2-fluoroaniline (8.4 g) in toluene (20 ml) was added to the reaction mixture at 73 ° C, followed by a toluene wash (5 ml). Trifluoroacetic acid (35 ml, 3.5 vol) was then added over a period of 10 minutes to the reaction mixture at 73 ° C and the reaction mixture was then stirred at that temperature for an additional 5 hours. The reaction mixture was cooled to 60 ° C and water (175 ml) was added over a period of 15 minutes. The reaction mixture was then heated to 68 ° C and stirred at that temperature for 8 hours. The paste was cooled to 20 ° C over 1 hour and the product was filtered and washed with water (20 ml). Yield: 1 1.24 g, 87%; NMR spectrum (DMSOd6) 8.72 (1 H, s), 8.02 (1 H, s), 1.16-1.13 (1 H, m), 7.56-7.50 (2H, m), 7.25 (1 H, s), 3.97 (3H, s); Mass spectrum (M + H) * = 454.0591.

EXAMPLE 9 Preparation of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazolin (the compound of Formula X) 7-hydroxy-4- ( 4-bromo-2-fluoroanilino) -6-methoxyquinazoline (100 g) and potassium carbonate (11.1 g) were suspended in N-methylpyrrolidinone (1070 ml) and stirred for 10 minutes before the addition of 1 ml. - (tert-butoxycarbonyl) -4- (4-methylphenylsulfoniumoxymethyl) piperidine (1 52.2 g). The reaction mixture was then heated at 95 ° C for 4 hours before being cooled again to 70 ° C. Then water (1 922 ml) was added over a period of 15 minutes. The reaction mixture was maintained at 73 ° C for 1 hour before cooling to 40 ° C and the product was isolated by filtration. The product was washed with water (549 ml), the slurry was washed with ethyl acetate (549 ml) at 50 ° C for 1 hour and then washed with ethyl acetate (275 ml) and dried at 50 ° C. Yield: 137 g, 86%; NMR spectrum (DMSOdfi) 1 .15-1 .3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, 1 H), 2.65-2.9 (m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, 1 H), 7.48 (d, 1 H), 7.55 (t, 1 H) , 7.65 (d, 1 H), 7.8 (d, 1 H), 8.35 (s, 1 H), 9.55 (br s, 1 H); Mass spectrum [ESI] (M + H) * = 561 -563.

EXAMPLE 10 Preparation of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxy-quinazoline (the compound of Formula X) 7-hydroxy-4 - (4-Bromo-2-fluoroanilino) -6-methoxyquinoline (5.0 g) and potassium carbonate (5.7 g) were suspended in N-methylpyrrolidinone (53.5 ml) and stirred for 10 minutes. 1 - (tert-butoxycarbonyl) -4- (4-methylphenylsulfonyloxymethyl) piperidine (7.6 g) was then added. The reaction mixture was then heated to 95 ° C and stirred at that temperature for 3.5 hours before being cooled again to 70 ° C. Isopropanol (25 ml) was added and then water (75 ml) was added over a period of 15 minutes. The reaction mixture was then stirred at 73 ° C for 1 hour before cooling to 40 ° C and isolating the product by filtration. The product was washed with water (27.4 ml) and dried at 50 ° C. Yield: 6.72 g, 87.2%; NMR spectrum (DMSOd6) 1 .1 5-1 .3 (m, 2H), 1 .46 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, 1 H), 2.65- 2.9 (m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, 1 H), 7.48 (d, 1 H), 7.55 (t, 1 H) ), 7.65 (d, 1 H), 7.8 (d, 1 H), 8.35 (s, 1 H), 9.55 (br s, 1 H); Mass spectrum fESIl (M + H) * = 561 -563.

EXAMPLE 1 Preparation of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (the compound of Formula X) 7-hydroxyl- 4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (9.7 g), sodium hydroxide (47% w / w, 5.0 ml) and Adogen® 464 (1.5 g) to water (50 ml) with agitation. 1 - (tert-butoxycarbonyl) -4- (4-methylphenylsulphonyloxymethyl) piperidine (1.0 g) as a solution in toluene (35 ml) was then added to the reaction mixture and heated at 70 ° C for 18 hours. The reaction mixture was then cooled to 20 ° C and the product was isolated by filtration. The product was then washed with toluene (20 ml) and dried at 50 ° C. Yield: 8.72 g, 77%; NMR spectrum (DMSOd6) 1 .1 5-1 .3 (m, 2H), 1 .46 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, 1 H), 2.65- 2.9 (m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, 1 H), 7.48 (d, 1 H), 7.55 (t, 1 H) ), 7.65 (d, 1 H), 7.8 (d, 1 H), 8.35 (s, 1 H), 9.55 (br s, 1 H); Mass spectrum [ESI] (M + H) * = 561 -563.

EXAMPLE 12 Preparation of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474) 7- (1-tert-butoxycarbonyl) piperidin-4- were added ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxy-quinazoline (100 g), water (80 ml), formic acid (120 ml) and aqueous formaldehyde (38% w / w, 28.2 g) to a vessel equipped with a top-head stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 80 ° C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 20 ° C and tetrahydrofuran (500 ml) was adynolated. The reaction mixture was heated to 40 ° C and tetrahydrofuran (500 ml) was added. The reaction mixture was heated to 40 ° C and sodium hydroxide (47% w / w), 265 ml) was added, followed by water (60 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 60 ° C and water (300 ml) and butyl acetate (300 ml) were added. The resulting mixture was stirred at 60 ° C for 15 minutes and then the aqueous phase was separated and discarded. Then water (400 ml) was added to the organic phase, which was stirred at 60 ° C for 15 minutes and then the aqueous phase was separated and discarded. Butyl acetate (300 ml) and tetrahydrofuran (50 ml) were added to the organic phase and set for distillation at ambient pressure. Distillation was stopped when the temperature of the contents reached 104 ° C. The paste was then cooled to 20 ° C and maintained for 2 hours before isolating the product by filtration. The product was washed with butyl acetate (300 ml) and dried at 50 ° C. Yield: 76.7 g, 90.6%; Spectrum of NMR (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s) , 3.97 (2H, d), 7.38 (1 H, ddd), 7.49 (1 H, dd), 7.64 (1 H, s), 7.88 (1 H, t), 7.89 (1 H, s), 9.01 ( 1 H, s), 1 0.37 (1 H, s); Mass spectrum (M + H) * = 475.

EXAMPLE 13 Preparation of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474) 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy ) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (35.0 g), water (28 ml), formic acid (42 ml) and aqueous formaldehyde (37% w / w, 8.2 g) were added to a vessel equipped with a top-head stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 80 ° C and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 40 ° C and tetrahydrofuran (175 ml) was added. Sodium hydroxide (47% w / w, 61.9 ml) was added at 40 ° C followed by water (21 ml). The aqueous phase was then separated and discarded. Water (420 ml) was added to the organic phase at 40 ° C over a period of 30 minutes. The paste was then cooled to 20 ° C before isolating the product by filtration. The product was washed with water (15 ml) and dried at 50 ° C. Yield: 27.1 g, 91.4%; NMR spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d) ), 7.38 (1H, ddd), 7.49 (1H, dd), 7.64 (1H, s), 7.88 (1H, t), 7.89 (1H, s), 9.01 (1H, s), 10.37 (1H, s); Mass spectrum (M + H) * = 475.

EXAMPLE 14 Preparation of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-methoxy) quinazoline (ZD6474) 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy ) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (100 g), water (45 ml), formic acid (120 I) and aqueous formaldehyde (37% w / w, 26.7 g) were added to a vessel equipped with a top-head stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 80 ° C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 60 ° C and methanol (800 ml) was added, followed by potassium hydroxide (49% w / w, 228 ml) over 2 hours. The paste was cooled to 20 ° C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (2: 1 methanohagua, 300 ml) and dried at 50 ° C. Yield: 79.6 g, 94%: NMR spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (1H, ddd), 7.49 (1H, dd), 7.64 (1H, s), 7.88 (1H, t), 7.89 (1H, s), 9.01 (1H, s) ), 10.37 (1H, s); Mass spectrum (M + H) * = 475.

EXAMPLE 15 Preparation of 4- (4-bromo-2-fluoroanilin) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474) 7- (1-tert-butoxycarbonyl) piper din-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (100 g), water (45 ml), formic acid (120 ml) and aqueous formaldehyde (37% w / w, 101.8 g) were added to a vessel equipped with a top-head stirrer and a reflux condenser and purged with nitrogen. The reaction mixture was heated to 80 ° C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 60 ° C and methanol (800 ml) was added, followed by potassium hydroxide (49% w / w, 228 ml) over 2 hours. The paste was cooled to 20 ° C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (2: 1 methanol: water, 300 ml) and dried at 50 ° C. Yield: 79.6 g, 94%; NMR spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2J6 (2H, m), 3.63 (3H, s), 3.97 (2H, d) ), 7.38 (1H, ddd), 7.49 (1H, dd), 7.64 (1H, s), 7.88 (1H, t), 7.89 (1H, s), 9.01 (1H, s), 10.37 (1H, s); Mass spectrum (M + H) * = 475.

EXAMPLE 16 Preparation of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methyl-pyridin-4-methylmethoxy) quinazoline (ZD6474) 7- (1-tert-butoxycarbonyl) piperidin-4 -ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline (36 g @ 100% w / w), water (16 ml), formic acid (44 ml) and aqueous formaldehyde (37% w / w, 36.4 g) were added to a vessel equipped with a top-head stirrer and a reflux condenser and purged with nitrogen. The reaction mixture was heated to 80 ° C over a period of 90 minutes and turned on at this temperature for 7 hours. The reaction mixture was then cooled to 60 ° C and methanol (376 ml) was added., followed by potassium hydroxide (49% w / w, 86 ml) over 2 hours. The paste was seeded with ZD6474 (methanolate form, 300 mg) and cooled to 20 ° C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (80:20 methanol, 67 ml) and dried at room temperature. Yield: 32.4 g, 95%; NMR spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.1 5 (3H, s), 2J6 (2H, m), 3.63 (3H, s) ), 3.97 (2H, d), 7.38 (1 H, ddd), 7.49 (1 H, dd), 7.64 (1 H, s), 7.88 (1 H, t), 7.89 (1 H, s), 9.01 (1 H, s), 10.37 (1 H, s); Mass spectrum (M + H) * = 475.

EXAMPLE 17 Purification of 4- (4-bromo-2-fluoroanilin) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474) 4- (4-bromo-2 fluoroanilino) -6-methoxy-7- (1-methyl piperidin-4-methoxy) quinazoline prepared as described in Example 9 (100 g) was suspended in tetrahydrofuran (500 ml), water (250 ml) and acetate of butyl (400 ml) and heated to reflux to allow dissolution. The mixture was then cooled to 60 ° C and the aqueous phase was separated and discarded. The organic phase was filtered. Tetrahydrofuran (50 ml) and butyl acetate (600 ml) were added to the organic filtrates and then heated to distill at ambient pressure until an internal temperature of 106 ° C was reached. The paste was then cooled to 5 ° C, filtered and washed with ethyl acetate (200 ml). The product was dried at 50 ° C. Yield: 91.8g, 91.8%: NMR spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 ( 2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (1 H, ddd), 7.49 (1 H, dd), 7.64 (1 H, s), 7.88 (1 H, t) , 7.89 (1 H, s), 9.01 (1 H, s), 10.37 (1 H, s); Mass spectrum (M + H) * = 475.

EXAMPLE 18 Preparation of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy) quinazoline (ZD6474) 7- (1-ester) butoxycarbon i) piperidin-4-yl methoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxy-quinazoline (40 g), water (160 ml), formic acid (43 ml) and aqueous formaldehyde (37% w / w, 33 ml) were added to a vessel with a top-head stirrer, reflux condenser and thermometer. The reaction mixture was heated to 81 ° C and stirred at this temperature for 5 hours. The reaction mixture was cooled to 60 ° C and tetrahydrofuran (1.78 ml) was added. The temperature of the reaction mixture was adjusted to 40 ° C and potassium hydroxide (49% w / w, 84 ml) was added, followed by water (22 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 60 ° C and water (1 07 ml) and butyl acetate (107 ml) were added. The aqueous phase was separated and discarded. The organic phase was filtered, followed by washing tetrahydrofuran (18 ml). The temperature of the filtrates was adjusted to 60 ° C and butyl acetate (107 ml) was added. The reaction mixture was adjusted for distillation at ambient pressure. The distillation stopped when the temperature of the contents reached 106 ° C. The paste was cooled to 65 ° C and tetrahydrofuran (107 ml) was added. The paste was cooled to 0-5 ° C and maintained for 1 hour before isolating the product by filtration. The product was washed with ethyl acetate (72 ml) and dried at 50 ° C. Yield: 24.82 g, 80.3%.

EXAMPLE 19: Diffraction of anhydrous ZD6474 X-ray powder The processes of the present invention synthesize the anhydrous form of ZD6474. The anhydrous form of ZD6474 is characterized by X-ray powder diffraction and is characterized to provide at least one of the following 2 theta values measured using CuKa radiation: 15.0 ° and 21.4 °. The anhydrous form of ZD6474 is characterized to provide a powder diffraction pattern of CuKa X-rays as shown in Figure 1. The ten most prominent peaks are shown in Table 1.

Table 1 The ten most prominent X-ray powder diffraction peaks for the anhydrous form of ZD6474 VS = very strong; S = strong Table 2 * The relative intensities are derived from measured defractograms with fixed slits. Analytical instrument: Siemens D5000, calibrated using quartz X-ray powder diffraction spectra is determined by mounting a sample of the crystalline ZD6474 material in Siemens simple silicon crystal tablet (SSC) assemblies and spreading the sample in a layer fine with the help of a microscope slide. The sample is rotated at 30 revolutions per minute (to improve counting statistics) and is irradiated with X-rays generated by a long thin-focus copper tube operated at 40kV and 40mA using CuKa radiation with a wavelength of 1.5406 angstroms. The fountain The X-ray aligned beam is passed through an automatic variable divergence slit set to V20 and the reflected radiation is directed through a 2mm anti-scatter slit and a 0.2mm detector slit. The sample is exposed for 1 second by 0.02 degrees of 2-theta increment (continuous scan mode) over the range of 2 degrees to 40 degrees of 2-theta in theta-theta mode. Run time is 31 minutes and 41 seconds. The instrument is equipped with a scintillation counter as detector. Data capture and control is through a Dell Optiplex 686 NT 4.0 workstation that operates with the Diffract + computation program. Those skilled in the X-ray powder diffraction technique will realize that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and proportions of non-unitary aspect that may affect the analysis of samples. The skilled person will also realize that the reflex position can be affected by the precise height at which the specimen is seated on the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample can also have a small effect. Hence, the diffraction pattern data presented will not be taken as absolute values. For more information on X-ray powder diffraction, the reader is referred to Jenkins, R &; Snyder, RL "Introduction to X-Ray Powder Diffractometry" (Introduction to X-ray powder diffractometry ", John Wiley &Sons, 1 996; Bunn, CW (1 948), Chemical Crystolography, Clarendon Press, London, Klug, H.P. &Alexander, LE (1974), X-Ray Diffraction Procedures.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: X-ray powder diffraction pattern for anhydrous ZD6474 - with the values of 2 theta plotted on the horizontal axis and the relative line intensity (counts) plotted on the vertical axis.

Claims

CLAIMS 1 . A process for the manufacture of a compound of the Formula lia: Where R is a suitable sulfonate ester; from a (C1-C6) alkyl-4-piperidinecarboxylate compound of Formula III: (C1-C6) alkyl III; said process comprises the steps of: (a) reacting the (C 1 -C 6) alkyl-4-piperidinecarboxylate compound of Formula III with di-tert-butylcarbonate in the presence of toluene or xylene to form a first mixture comprising toluene or xylene, tert-butanol and a compound of Formula IV: (C1-C6) alkyl IV; (b) substantially removing the tert-butanol from the first mixture; (c) reacting the compound of Formula IV with a suitable reducing agent in situ in the presence of toluene or xylene to form a second mixture comprising toluene, reduction by-products including alcohol by-products and a compound of the Formula V: V; (d) substantially removing the alcohol by-products of the second mixture; and (e) reacting the compound of Formula V with a suitable sulfonylating agent in situ to form a sulfonate ester in the presence of a suitable base and toluene to form the compound of Formula Ia.
2. A process according to claim 1, wherein the compound of Formula Ia is a compound of Formula I I and the sulfonating agent is tosyl chloride. II 3. A process according to claim 1 or 2, wherein the (C1-C6) alkyl-4-piperidinecarboxylate compound of Formula I1 is ethyl 4-piperidinecarboxylate. 4. A process according to claim 1 or 2 or 3, wherein in step (c) the reducing agent is selected from bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride and diisobutylaluminum hydride. 5. A process according to claim 4, wherein in step (c) the reducing agent is sodium bis (2-methoxyethoxy) aluminum hydride. 6. A process according to any of claims 1 to 5, wherein in step (e) the base is triethylene diamine. 7. A process according to any of claims 1 to 6, further comprising step (f) of isolating the compound of Formula I ia. 8. A process according to claim 7, wherein step (f) comprises crystallization using a solvent system of toluene and isohexane. 9. A process for the manufacture of a compound of Formula VI: VI wherein R1 is an acid-labile protecting group of a compound of the Formula VII: VII said process comprises the steps of: (g) reacting the compound of Formula VII with a suitable chlorinating agent in the presence of a suitable base and a suitable solvent, wherein the reaction is performed at: (g-1) adding a mixing the compound of the Formula VI and the base in the solvent to a mixture of the chlorinating agent in the solvent at a temperature in the range from 60 to 90 ° C over a period of about 60 minutes; or (g-2) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at room temperature over a period of about 15 minutes and then heating the reaction mixture over a period of about 90 minutes at a temperature in the range from 70 to 90 ° C and stirring the reaction mixture at that temperature for about 1 hour; or (g-3) adding the chlorinating agent to a mixture of the compound of the Formula VI and the base in the solvent at a temperature in the range from 60 to 1 10 ° C over a period of about 15 minutes, to form a composed of Formula VI II: VIII; Y (h) reacting the compound of Formula VI II with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form a hydrochloride salt of the compound of Formula VI; and subsequently the compound of Formula VI obtained in the form of the hydrochloride salt can be converted into the free base or in the form of an alternative salt, if required. 10. A process according to claim 9, wherein steps (g) and (h) are both conducted in toluene. eleven . A process according to claim 9 or 10, wherein the chlorinating agent used in step (g) is phosphorus oxychloride. 12. A process according to any of claims 9 to 11, wherein the base used in step (g) is selected from triethylamine and N, N-diisopropylethylamine. 1 3. A process according to any of claims 9 to 12, further including step (!) Of isolating the compound of the Formula SAW . 14. A process for the manufacture of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, a compound of Formula IX: IX of a compound of the Formula Vi l: vp wherein R1 is an acid-labile protecting group said process comprises the steps of converting the compound of Formula VII to a compound of Formula VI: VI in conducting a process according to any of claims 9 to 12; and (j) removing R1 from the compound of Formula VI in situ in the presence of the solvent used in steps (g) and (h) to form the compound of Formula IX or a salt thereof; and subsequently the compound of the Formula IX obtained in the free base form can be converted into a salt form and the compound of the Formula IX obtained in the form of a salt can be converted into the free base or the salt form alternative, if necessary. 5. A process according to claim 14, wherein R1 is benzyl and in step (j) the benzyl group is removed in situ by reaction with trifluoroacetic acid at a temperature in the range of 60 to 80 ° C. 16. A process according to claim 14, wherein R is benzyl and the benzyl group is removed in the presence of trifluoroacetic acid and the compound of Formula IX is converted to a trifluoroacetic acid salt by the addition of potassium hydroxide or the addition of sodium hydroxide and water. 17. A process for the manufacture of 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, a compound of Formula IX: IX from a compound of the Formula VI: vu said process comprises the steps of converting the compound of the Formula VII to a compound of the Formula VI: VI when conducting a process according to claim 1 3; and (k) removing R1 from the compound of Formula VI to form the compound of Formula IX or a salt thereof; and subsequently the compound of the Formula IX obtained in the free base form can be converted into a salt form and the compound of the Formula IX obtained in the form of a salt can be converted into the free base or the salt form alternative, if necessary. 18. A process according to claim 17, wherein R is benzyl and in step (k) the benzyl group is removed by reaction with a suitable hydrogenation agent. 19. A process for the manufacture of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-bromo-2-fluoroanilino) -6-methoxyquinazoline, a compound of Formula X: X from a compound of the Formula Vi l: Said process comprises the steps of converting the compound of the Formula VII to a compound of the Formula IX: IX when conducting a process according to any of claims 14 to 17; and (I) reacting the compound of Formula IX with a compound of Formula I I: p in the presence of a suitable base to provide a compound of Formula X or a salt thereof; and subsequently the compound of Formula X obtained in the free base form can be converted into a salt form and the compound of Formula X obtained in the form of a salt can be converted to the free base or salt form alternative, if necessary. 20. A process according to claim 1, wherein the base used in step (I) is selected from sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. twenty-one . A process according to claim 19 or 20, further comprising step (m) of isolating the compound of Formula X. 22. A process for the manufacture of 7- (1-tert-butoxycarbonyl) piperidin-4-ylmethoxy) -4- (4-Bromo-2-fluoroanilino) -6-methoxyquinazoline, a compound of Formula X: X from 7-hydroxy-4- (4-bromo-2-fluoroanilino) -6-methoxy-quinazoline, a compound of Formula IX: IX said process comprises the steps of: (I) reacting the compound of Formula IX with a compound of Formula I I: p in the presence of a suitable base to provide a compound of Formula X or a salt thereof; and (m) isolating the compound of Formula X by: (m-1) adding water and allowing the crystallization of the compound of Formula X to occur, collecting the compound of Formula X and washing the compound of Formula X with water , followed by a solvent selected from ethyl acetate, butyl acetate and acetonitrile at a temperature in the range from 25 to 55 ° C; or (m-2) adding water and an alcohol selected from methanol, ethanol, isopropanol and n-propanol and allowing the crystallization of the compound of Formula X to occur, collecting the compound of Formula X and washing the compound of Formula X with a mixture of water and the alcohol selected from methanol, ethanol, isopropanol and n-propanol, followed by a solvent selected from ethyl acetate, butyl acetate and acetonitrile at a temperature in the range from 25 to 55 ° C; and subsequently the compound of Formula X obtained in the free base form can be converted to a salt form, and the compound of Formula X obtained in the form of a salt can be converted to the free base or in the form of a alternative salt, if necessary. 23. A process according to claim 22, wherein the base used in step (I) is selected from sodium carbonate and potassium carbonate. 24. A process according to any of claims 19 to 23, wherein the compound of the Formula I I used in step (I) is prepared according to the process according to any of claims 1 to 8. 10 25. A process for the manufacture of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline, ZD6474: ZD6474 from a compound of Formula X: said process comprises the steps of: (n) reacting the compound of Formula X with formic acid and formaldehyde or a formaldehyde polymer to form a formic acid salt of ZD6474; (o) adding an inert organic solvent and a suitable base in order to form the free base of ZD6474; eleven subsequently the ZD6474 obtained in the free base form can be converted to a pharmaceutically acceptable salt, if necessary. 26. A process according to claim 25, wherein step (n) is carried out in water at a temperature in the range from 70 up to 90 ° C. 27. A process according to claim 25 or claim 26, wherein the inert organic solvent used in step (o) is selected from tetrahydrofuran, butyronitrile and methanol. 28. A process according to any of claims 25 to 27, wherein the base used in step (o) is selected from sodium hydroxide and potassium hydroxide. 29. A process according to any of claims 25 to 28, wherein the compound of Formula X used in step (n) is prepared according to the process according to any of claims 19 to 24. 30. A process according to any of claims 25 to 29, which further comprises further purifying ZD6474 in a mixture of tetrahydrofuran, water and butyl acetate to provide the crystalline anhydrous form.