A short review on synthetic strategies towards quinazoline based anticancer drugs

Quinazolines belong to one of the most important classes of heterocyclic compounds owing to their diverse medicinal properties. The synthesis of novel quinazoline derivatives has been a main focus of many researchers during last decades due to the broad scope of this moiety. There are many commercial drugs available with a quinazoline motif and several compounds are in the preliminary development of potential bioactive compounds. This motif is being utilized in drug targets for the treatment of various diseases owing to the anti-cancer, anti-bacterial, anti-inflammatory, anti-malarial and anti-hypertensive activities. This review describes some of synthetic strategies used for manufacturing aminoquinazoline based anticancer drugs on both bench and industrial scales.


Introduction
Examining practices of medicinal chemistry is enriching as well as challenging.A definitive objective is the advancement of drugs in various therapeutic areas and understanding their mechanism of action.Despite the discovery of many selective and potent drugs that prevent diseases, alleviate pain, and manage the treatment of diseases afflicting humans, challenges to invent safer and efficacious drug molecules still remains. 1 With the development of new tools to expedite drug discovery, the role of organic chemists to synthesize novel drug molecules of biological importance is pivotal to treat various diseases.Organic compounds specifically heterocyclic compounds are of paramount importance as more than half of all known organic compounds are heterocyclic.Synthesis of novel heterocycles in the laboratory has revolutionized the course of medical science.There are many classes of heterocyclic compounds which are being used as drugs for relief from various diseases.It has been observed that compounds containing heterocycles such as pyridine, pyrimidine, indole, thiazolidine-2,4-dione (TZD) and quinazoline etc. are central to the core of many therapeutic drugs.

Quinazoline Derivatives as Drug Target
The synthesis of quinazoline itself was first reported by Gabriel in 1903.The presence of a fused benzene ring alters the properties of the pyrimidine ring considerably.The properties of substituted quinazolines largely depend on the nature of the substituents and whether they are on the pyrimidine ring or on the benzene ring. 2 Quinazoline derivatives are the central core of many complex natural products, which have been isolated from different plants and microorganisms. 3,46] Biological activities of quinazoline derivatives are very well established and there are numerous drugs available in the marketplace (Figure 1).This review summarizes the synthetic strategies which have been utilized for aminoquinazoline based commercial anti-cancer drugs on both bench and industrial scales.Though it has been our effort to compile all relevant work, there may be additional references that we have inadvertently missed.

Quinazoline Moiety as Anti-cancer Drug Target
There has been a considerable development of promising quinazoline derivatives for cancer treatment during the last few decades.These are well known to inhibit epidermal growth factor receptor (EGFR) protein, albeit that a large panel of other therapeutic protein targets is also there. 7EGFR is a member of the tyrosine kinase receptor family.It is a cell membrane receptor which has an extracellular ligand binding domain and an intracellular tyrosine kinase domain.These trans-membrane receptors bind to ligands which lead to the homoor hetero dimerization of the receptor, which results in trans-phosphorylation of tyrosine residues.These downstream signaling pathways regulate cell division, motility, adhesion and apoptosis.It has been observed that high levels of EGFR expression are present in many tumor cells. 8,9 number of quinazoline derivatives have been approved by the FDA and novel quinazoline derivatives are being investigated as anti-cancer drugs from last two decades.Some of the clinically approved quinazoline derivatives have been depicted in Figure 2. Synthesis of these drug targets from medicinal chemistry scale to efficient, commercially viable and multi-gram scale preparations has been a challenging and thoughtful journey for synthetic chemists.We will describe the synthetic strategies involved for these aminoquinazolines in the following sections of this article.

Synthetic Strategies Towards Quinazoline Based Anticancer Drugs
Synthetic strategies utilized for synthesis of quinazoline based anticancer drugs is discussed in subsequent sections: 4.1.Afatinib (Gilotrif®, Giotrif®, Afanix®-Boehringer Ingelheim Pharmaceuticals, Inc.) Afatinib (A) (Figure 3) is a medication which has been used for metastatic non-small cell lung carcinoma (NSCLC). 10It is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinases. 11It is the first lung cancer treatment drug.The drug passed the fast-track approval channel of the US FDA in 2008.It was approved as drug in 2013.

Scheme 1. Initial synthesis of Afatinib (A).
Since this synthetic strategy first prepares the quinazoline core and then performs the side chain attachments, the overall yield is low and most steps need to be purified by column chromatography.Therefore, this synthetic approach is not suitable for an industrial scale synthesis.
Xuenon et al. reported a preparation method that has easy-to-obtain raw materials, is a simple process, is economical and ecofriendly.This approach is advantageous for the industrial production of the drug (Scheme 2). 15The process involves nitration of p-hydroxybenzonitrile A7 in the presence of nitric acid and sulphuric acid to form 4-hydroxy-3-nitrobenzonitrile A8.Reaction of S-tetrahydrofuran-3-ol A2 with A8 in the presence of DIAD yielded the corresponding ether compound A9.Reduction of the nitro group of A9 using FeCl3 afforded the corresponding amine A10 in good yield.A10 and E-4-(dimethylamino)but-2-enoyl chloride A11 undergo amidation to produce A12.Nitration of A12 afforded A13 which was reduced in the presence of Pd/C to form amine A14.Cyclization followed by amination of A14 afforded Afatinib A. This process involves classical reactions and easily available starting materials, which are suitable for industrial scale synthesis.
The conversion of G13 to nitrile G17 is achieved with a reasonably high yield through the formation of an oxime intermediate G15.The synthesis of quinazoline G19 was performed by reacting ortho-nitrobenzonitrile G18 with a reducing agent such as FeCl3/N2H4.H2O and in situ cyclisation with HCl-formic acid.Chlorination followed by amination with 4-chloro-3-fluoroaniline G7 yielded gefitinib (G) in good yields.

Scheme 4. Industrial scale synthesis of gefitinib (G).
Chandregowda et al. later reported an improved convergent approach for commercial synthesis of G. 21 The convergent process (Scheme 5) developed for the preparation of gefitinib involves reducing nitro group of ortho-nitrobenzonitrile G18 with Na2S2O4.H2O to form G19. G19 is reacted with DMF.DMS to synthesize N'-2-cyano-4,5-{bis(2-methoxyethoxy)phenyl}-N,N-dimethylformamidine G20 which was further reacted by 3chloro-4-fluoroaniline G7 to get gefitinib (G).This process permits a reduction in the number of steps used and with higher yields.

Erlotinib (Tarceva® -Roche Pharmaceuticals)
Erlotinib (E) (Figure 5) is an inhibitor of the EGFR-TK that is used in the treatment of non-small cell lung cancer, pancreatic cancer and several other types of cancer.It is typically marketed under the trade name Tarceva. 23UTHOR(S) Figure 5.Chemical structure of erlotinib (E).

Synthesis of Erlotinib (E)
. The initial synthesis of E was reported by Schnur et al. in 1998.The two hydroxyl groups on ethyl 3,4-dihydroxybenzoate E1 were alkylated with 1-bromo-2-methoxyethane E2 to afford potassium salt of 3,4-bis(2-methoxyethoxy)benzoate E3.E3 undergoes a nitration reaction in the presence of nitric acid to afford the corresponding nitro E4 which was reduced and esterified to afford E5.Cyclization of E5 yielded quinazolin-4(3H)-one E6.Chlorination followed by substitution with 3-ethynylaniline E8 afforded E (Scheme 7). 24In this approach, 4-chloro quinazoline E7 is a key intermediate and its synthesis involves the use of corrosive and toxic reagents such as oxalyl chloride, a highly flammable gas such as hydrogen at high pressure and costly reagents such as platinum oxide.

Scheme 7. Initial synthesis of erlotinib (E).
Considering these difficulties Ramanadham et al. developed a simple and economically viable process for the preparation of Erlotinib (E) (Scheme 8). 25 The basic raw material selected for synthesis is 6,7dimethoxyquinazolin-4(3H)-one E9.E9 was reacted with aqueous HBr to synthesize dihydroxy E10.The acetylation of E10 with acetic anhydride and pyridine formed the corresponding bis-acylated derivative E11.The carbonyl group of E11 was converted in to leaving group 'Cl' using oxalylchloride under reflux conditions to afford intermediate E12 which was condensed in situ after workup with 3-ethynylaniline E8 under reflux conditions to afford E13.E13 was de-acylated with aqueous ammonia to form E14 which was further reacted with 2-iodo-ethylmethylether E15 in the presence of base to synthesize E16 which was converted into Erlotinib hydrochloride by treatment with HCl in propan-2-ol.

Scheme 8. Synthesis of erlotinib (E).
Chandregowda et al. reported simplified conditions for the synthesis of E (Scheme 9). 26Their approach involves a similar synthetic process for synthesis of E7 as depicted in Scheme 8. Treatment of E7 with 3ethynylaniline E8 in DMF without using extra base afforded erlotinib (E) as the hydrochloride salt.

Dacomitinib (Vizimpro® -Pfizer Inc.)
Dacomitinib (D) (Figure 6) is a second-generation tyrosine kinase inhibitor and used for the treatment of nonsmall-cell lung carcinoma (NSCLC).It is characterized by the irreversible binding at the ATP domain of the epidermal growth factor receptor family kinase domains.Dacomitinib was developed by Pfizer Inc. and approved by the US FDA in 2018.

Synthesis of dacomitinib (D).
The synthesis of this is mainly divided into two parts viz.synthesis of the quinazoline and synthesis of the crotonate.In the lab scale synthesis, [29][30][31] the quinazoline moiety was synthesized from 2-amino-4-fluorobenzoic acid D1 (Scheme 11).D1 was cyclized with formamidine D2 to form 7-fluoroquinazolin-4(3H)-one D3 which undergoes nitration to get D4, Chlorination to form intermediate D5, amination with G7 to afford D6 followed by O-methylation afforded D7.Reduction of the nitro group in D7 to amine in presence of Raney Ni afforded the desired quinazoline D8.Synthesis of (E)-4-bromobut-2-enoyl chloride D11 was done by hydrolysis of methyl (E)-4-bromobut-2-enoate D9 to form the corresponding acid D10 which was followed by acyl chloride formation.This intermediate was used to couple with quinazoline D8 to form the corresponding amide D12.D12 was reacted with piperidine D13 to afford D. The disadvantage of this approach is that the cost is high, column purification is needed in 2-3 steps and overall yield is low especially for last step in which substitution with pyridine was needed to produce D.

Scheme 11. Lab scale synthesis of dacomitinib (D).
This last approach was further improved by slight modification in some of the reaction conditions and alterations in reaction sequences. 32 afforded D15 in excellent yield and regioselectivity. 33Condensation of D15 with amidine acetate D2 yielded intermediate D16, which was crystallized from the reaction mixture to afford a pure compound.

Scheme 12. N-arylation route to dacomitinib (D).
The chlorination of D16 was conducted in a mixture of toluene and acetonitrile.This mixture of solvents also served well during the nucleophilic aromatic substitution to afford D18.Therefore, D18 was produced through telescoped process from D16 via D17 over two steps.Palladium catalyzed N-arylation with D19 was done at this stage to form D. The initial synthesis route was significantly improved to enable the delivery of kilo scale synthesis by changing reagents, solvents and conditions in due course.The medicinal chemistry route was changed in order to meet the API demand for pre-clinical and clinical studies.An efficient three-step process was developed to manufacture dacomitinib (D) on a commercial scale by utilizing the Dimroth Rearrangement for cyclization. 34The nitro group reduction of D20 was performed with Pd/C carbon catalysts using acetonitrile as solvent to enable telescoping with the next step to afford D21.Propanephosphonic acid anhydride (T3P ® ) solution in acetonitrile in the presence of 2, 6-lutidine was used for the coupling reaction to afford D23 without isolation of intermediate D21.A Dimroth reaction in acetic acid in acetonitrile at 30 °C afforded D (Scheme 13).

Scheme 14. Synthesis of lapatinib (L).
A new pathway for the synthesis of this was reported in which the hydroxyl group of 6iodoquinazoline-4-ol is protected by the tetrahydropyranyl group hence entailing greater solubility of the intermediates in common organic solvents the lack of which was a major disadvantage of the process discussed above. 37Keeping in mind the difficulties for the preparation of Lapatinib L on a commercial scale, Prasad et al. developed a simple, economically viable and commercially applicable process for the preparation of lapatinib L. 32 This process involved the reaction of 3-chloro-4-(3-fluorobenzyloxy)-aniline L4 with N, Ndimethylformamide dimethylacetal L14 carried out in the presence of acetic acid to afford L15.Reaction of 2aminobenzonitrile L16 with iodinemonochloride ICl in acetic acid yielded L17 which underwent Dimorth Rearrangement with L15 in acetic acid to afford L18.S-M coupling of L18 with (5-formylfuran-2-yl)boronic acid L7 afforded the corresponding aldehyde L19.Imination followed by reduction of L19 yielded lapatinib L which was converted to its pharmaceutically acceptable ditosylate monohydrate salt L.TSOH (Scheme 15).

Vandetanib (Caprelsa® -AstraZeneca)
Vandetanib (V) (Figure 8) is a kinase inhibitor of tumor angiogenesis and cell proliferation with the potential for use in a broad range of tumor types.Vandetanib was approved in 2011 by the US FDA to treat unresectable, locally advanced, or metastatic medullary thyroid cancer in adult patients. 38gure 8.Chemical structure of vandetanib (V).

Scheme 16. Initial synthesis of vandetib (V).
The synthesis started from the inexpensive building block 4-hydroxy-3-methoxybenzonitrile V16 (Scheme 17), which was alkylated with benzyl bromide V17 to form intermediate V18.Nitration of V18 under mild conditions afforded V19 in good yield.Selective reduction was done using sodium dithionite to afford V20.Compound V20 was reacted with large excess of DMF-DMA to aid solubility and formation of the formamidine V21.Microwave irradiation for 30 minutes at 90 °C afforded V21 in 95 % yield while conventional heating at the same temperature provided V21 in a reduced yield of 58% despite extending the reaction time to 120 minutes.TFA-mediated debenzylation of V21 yielded V22.Alkylation of V22 using tert-butyl-4(tosyloxy)methyl)piperidine-1-carboxylate V14, which was synthesized by the method afforded V23.The key Dimroth rearrangement step was conducted in the presence of 4-bromo-3-fluoroaniline V8 and acetic acid with microwave heating at 130 °C for 45 minutes to afford V15.The penultimate step in the synthesis of V was the Boc deprotection of piperidine, which was done as per above procedure.

Scheme 17. Synthesis of vandetib (V).
The quinazoline motif has been further explored for more potent anticancer agents and sapitinib S (AZD8931) is being studied as a more potent ATP competitive inhibitor of EGFR and erbB2.Compared to gefitinib or erbB2 inhibitors, AZD8931 was a much more potent inhibitor of EGF-driven cellular proliferation in multiple tumour cell lines 46 William et al. reported an industrial scale synthesis using Dimroth rearrangement route as has been shown to be utilized to some of commercially available drug of this series. 47ll in all, Dimroth Rearrangement is the most versatile method to synthesize amino quinazoline derivatives.A general synthetic approach for isolation of such compounds is depicted in Scheme 18. Scheme 18.General approach for synthesis of amino quinazoline.
Therefore, it is worth to mention general mechanism of Dimroth Rearrangement for such derivatives which is given in Figure 9.

Future perspective of quinazoline based heterocyclic compounds
Since quinazoline motif is highly prevalent in pharmaceutical compounds specifically anti-cancer drugs, novel scaffolds are being synthesized and investigated as biologically active compounds.This motif has broad for synthesis of novel compounds due to diverse reactive positions for derivatization.Piperazine based quinazoline derivatives have been reported recently, which are being investigated preventing neurodegenerative diseases such as Parkinson's disease (PD). 48V. K. Sharma et al recently reported efficient and versatile one-pot sequential synthesis of quinazolin-8-ol derivatives employing heterogeneous catalyst for S-M coupling. 49

Conclusions
This review of literature summarizes several synthetic methods for industrial and small-scale quinazoline based anti-cancer drugs.The use of quinazolines for the treatment of various diseases has motivated researchers to improve synthetic approaches and overcome challenges of industrial-scale synthesis.There is a variety of strategies developed for synthesis of such drugs, but the Dimroth rearrangement dominates the

Figure 2 .
Figure 2. Quinazoline derivatives approved by the FDA as anti-tumor agent.
Yu et al. developed N-arylation route (Scheme 12) in which easily available 2-amino-4-methoxybenzoic acid D14 was used as starting material.Iodination of D14 using N-Iodosuccinimide AUTHOR(S)