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Download-PDF Journal of Pharmaceutical Research International 27(6): 1-15, 2019; Article no.JPRI.44928 ISSN: 2456-9119 (Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919, NLM ID: 101631759) An Overview of Different Synthetic Routes for the Synthesis of Phthalazine Derivatives Smita Singh1,2 and Nitin Kumar3* 1IFTM University, Muradabad, Uttar Pradesh, India. 2K. N. Modi Institute of Pharmaceutical Education and Research, Modinagar, Uttar Pradesh, India. 3Department of Pharmacy, Sushant School of Health Sciences, Ansal University, Gurugram, 122003, India. Authors’ contributions This work was carried out in collaboration between both authors. Both authors read and approved the final manuscript. Article Information DOI: 10.9734/JPRI/2019/v27i630189 Editor(s): (1) Dr. Carlos M. Contreras, Unidad Periferica Xalapa, Instituto de Investigaciones Biomedicas, UNAM, Mexico and Instituto de Neuroetologia, Universidad Veracruzana, Mexico. (2) Dr. Jinyong Peng, Professor, College of Pharmacy, Dalian Medical University, Dalian, China. (3) Dr. Ali Nokhodchi, Professor of Pharmaceutics and Drug Delivery, School of Life Sciences, University of Sussex, UK. Reviewers: (1) Sangeetha A/P Arullappan, Jalan Universiti, Malaysia. (2) Manojit Pal, University of Hyderabad, India. (3) B. Satish Jadhav, Balbhim College, India. Complete Peer review History: http://www.sdiarticle3.com/review-history/44928 Received 14 October 2018 Review Article Accepted 31 December 2018 Published 08 June 2019 ABSTRACT This review paper describes the different synthetic routes used for the synthesis of substituted phthalazine derivatives. Phthalazines have been used as building blocks for the synthesis of a new molecule with heterocyclic structure. These new molecules are highly useful in medicinal chemistry for the researchers leading to the further development of new molecules which have potency and effectiveness to produce a desired pharmacological response. Keywords: Phthalazine; phthalazinone; thiazolo; phthalic anhydride. 1. INTRODUCTION discovery of the first naturally occurring pyridazine derivative was a milestone in the Phthalazines are a unique well-known class of recognition of the potential of 1, 2-diazine core nitrogen-containing heterocyclic compounds. The nucleous as a valuable unit in medicinal _____________________________________________________________________________________________________ *Corresponding author: E-mail: [email protected]; Singh and Kumar; JPRI, 27(6): 1-15, 2019; Article no.JPRI.44928 chemistry [1]. Hydralazine also has been used inhibitors [8,9], cardiotonic [10], antitumor pharmacologically as anti-hypertensive and [11,12,13], vasorelaxant [14], antibacterial [15], vasodilating agent [2]. More recently, some 3,6- antimicrobial [15], antioxidant [16], antidiabetic substituted phthalazines have been reported as a [17] and anticonvulsant [3,5,18]. Various pharmacologically active scaffold for established drug molecules like budralazine [16] anticonvulsants activity. and Azelastine [8,19] are prepared from the corresponding phthalazine-1- one. Phthalazines are important building blocks in the construction of a new molecular system for The current review paper suggests new ways for biologically active molecules [3,4,5]. The researchers to develop more effective and safer development of new and efficient methodologies drugs hence may be imperative and challenging for the potentially bioactive 4- in medicinal chemistry [20]. hydrazinophthalazine-1-one derivative is important. 2. SYNTHESIS OF PHTHALAZINE Mostly, 4-hydrazinophthalazine-1-one is used as DERIVATIVES BY VARIOUS starting material for the synthesis of various SYNTHETIC ROUTE derivatives. Triazolo phthalazine is also considered as pharmacologically highly active Robert W. Carling et al. reported the synthesis of molecule having different pharmacological 3-phenyl–6-(2 pyridyl) methyloxy -1, 2, 4- triazolo activities like anti inflammatory [6,7], PDE4 (3, 4 - a) Phthalazines derivatives. scheme-1 NHNH2 N N i,ii N N NH NH OCH3 O O 2 1 iii N N N N N N NH NH OCH OCH3 3 O O Reagents: (i)4methoxy benzoyl chloride,Et3N,1,4dioxane,room temp;(ii) DMF,reflux(iii)NaH,DMF,Ph2Br 100 temp. scheme-2 N N NHNH2 N i,ii N NH NH O O 5 v 1 iv iii N N N N N N N NH N N O NH CH NH 3 O O R 8-17 7 Reagents: (i)benzoyl chloride,Et3N,1,4 dioxan,room temp;(ii) DMF, reflux (iii) NaH,DMF,PhCH2Br,100 temp (iv) NaH,DMF,CH3I (V)NaH,DMF,RCH2Br or RCH2Cl. 2 Singh and Kumar; JPRI, 27(6): 1-15, 2019; Article no.JPRI.44928 scheme-3 Cl N N N N i N N ii N N NH NH Cl O Cl R iii N N N N ii N R N R1 1 NH NH O Cl R 2 Reagents: (i) PhCONHNH2, Et3N, Diaxone, reflux; (ii)ROH, NaH, DMF; (iii)R1CONHNH2,Et3N, Xylene, Reflux; (iv)R1COCl, Et3N, Diaxone, reflux. scheme-4 O Cl O H H i N ii N O N N H H O CH O CH3 Cl CH3 3 45 46 iii,iv 47 N N CH3 N N N N NH NH CH Cl Cl 48 3 49 v v CH3 N N N N N N NH NH O CH3O N N 51 50 Reagents: (i) NH2NH2.H2O, AcOH,NaOAC,reflux; (ii) POCl3,reflux,(iii) PhCONHNH2, Et N,xylene,reflux(iv) chromatography;(v) ROH, NaH, DMF. 3 Lei Zhang introduced a new series of derivatives that contains 6 – alkoxy – (1,2,4,) triazolo (3, 4 -a) phthalazines nucleus. 1, 4 dichlorophthalazine proceeded for reaction with formic hydrazide and appropriate alcohol in the presence of xylene. (Shown in Table-1) to produce a number of phthalazine derivatives. Scheme-5 Cl Cl OR N HCONHNH2 ROH N N N xylene,reflux N NaOH,DMF N reflux,3hr. Cl N N N N 1,4 dichloro phthalazine 5-b 5c-w 3 Singh and Kumar; JPRI, 27(6): 1-15, 2019; Article no.JPRI.44928 Table 1. Different R substituent’s showed below (5c-5w) 5c -C6H5 5j-C10H7 5q-C3H7 5d -C6H4(O-CH3) 5k-C6H4(o-OCH3) 5r-n-C4H9 5e- C6H4(m-CH3) 5l-C6H4(p-OCH3) 5s-n-C6H13 5f-C6H4(p-CH3) 5m - C6H4(p-NO2) 5t-nC7H15 5g-C6H4(p-F) 5n- C6H4(p-NH2) 5u-nC8H17 5h-C6H4(p-Cl) 5o-CH3 5v-nC10H21 5i-CH2C6H3(2,4-Cl2) 5p-C2H5 5w-nC5H11 A new series of 6 – alkoxy (1, 2, 4) triazolo (3, 4 - phthalazine- 3(2H)-one derivatives. (Cheng –Xi a) phthalazine – 3 (2H) one was prescribed by et al., 2011). Ching in 2011 using appropriate amount of 1- chloro- 4 – alkoxy phthalazine as starting For the synthesis of 2 – (4 – (4 phenoxyphenyl) material and reacting it with methyl hydrazine phthalazine – 1 – yl) – malononitrile, an carboxylate. 1 chloro – 4 – alkoxy phthalazines equimolar amount of chlorophthalazine (0.01 (6d-u) were synthesized from phthalic anhydride. mol) was made to react with ethylene in ethanol (6d-u) further treated with hydrazine hydrate in containing sodium ethoxide. This reaction the presence of ethanol to yield 6-substituted 1, mixture was refluxed for 6 hours at 70°C 2, 4 triazolo [3,4-a] phthalazin-3(2H)-one temperature. After the completion of the reaction derivatives. the reaction mixture was poured into ice. The solid was collected and washed with a suitable 2,3 dihydrophthalazine 1,4 dione further reacted solvent to give respective derivatives. with phosphorous oxychloride to give 1,4 di chlorophthalazine which then reacted with A mixture of (2-(4-(4-phenoxyphenyl) phthalazin- appropriate alkanol and substituted phenol in 1-yl) malononitrile (0.1 mol), ethyl 2-cyano-2-(4- dimethyl formamide to give different (4-phenoxyphenyl)phthalain-1yl) acetate (0.01 derivatives. These derivatives were used as a mol) and hydrazine hydrate (0.01 mol) in reactant to react in the presence of dimethyl methanol (20 ml) were taken in round bottom sulfoxide with methyl hydrazine carboxylate. In flask and refluxed for 6 hour, then allowed to cool this way, the researcher was able to produce a and product was collected by filtration and finally series of 6-alkoxy (1,2,4) triazolo (3,4-a) recrystalized using appropriate solvent. Scheme-6 O O Cl NH2NH2H2O NH POCl3 N O NH N O O Cl 6-c 6-b 6-a ROH OR OR NH NHCO CH N 2 2 3 N N N O N NH Cl 6d-u 7d-u Table 2. Different R substituent’s shown below (7d-7u) 7d = n-C4H9 7j= -C6H5 7p =-C6H4 (4-Br) 7e= n-C5H11 7k= -C6H4 (4-F) 7q= -C6H4 (2-CH3) 7f = n-C6H13 7l= -C6H4(2-Cl) 7r= -C6H4 (3-CH3) 7g = n-C7H15 7m= -C6H4(3-Cl) 7s= -C6H4 (4-CH3) 7h = n-C8H17 7n = -C6H4(4-Cl) 7t= -C6H4 (2-OCH3) 7i= n-C10H21 7o= -C6H3(2,4-Cl2) 7u= -C6H4 (4-OCH3) 4 Singh and Kumar; JPRI, 27(6): 1-15, 2019; Article no.JPRI.44928 scheme-7 N N NC CN H N NH NC CN 2 2 C NH NH H2 N 2 2 N N N Cl Ar Ar N N NC COOEt N N Ar H2N NH2 CNCH2COOEt NH2NH2 N N N N PhO Ar Ar Ar= Scheme-8 N N Ph N benzoyl hydrazine N PhCONHNH 2 Ar N N Ph sodium azide N N NaN3 Ar H Cl N OCH3 N p-anisidine N N N Ar Ar NH2 N CH3COONH4 N N N Ar NH N 2 NH2NHCSNH2 N NHNH2 Ar NH2NH2 N N PhO Ar Ar= Synthesis of 4- (4 – (4- phenoxyphenyl) phthalazine – 1- yl) 4H – pyrazole – 3, 5 di – amine In this scheme (8), chlorophthalazine was chlorophthalazine was treated with Para reacted with benzoyl hydrazine using n-butanol anisidine to give phthalazine derivatives. as a solvent. Under the refluxed condition, it gave 6 – (4 – phenoxy phenyl) – 3 phenyl – (1, 2, When chlorophthalazine was reacted with 4) triazolo (3, 4-a) phthalazine.This is further ammonium acetate it gave amino phthalazine. treated with sodium azide.
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