A Review on Synthetic Protocols of Pyridazine and Pyridazone Analogues

Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71

INDO GLOBAL JOURNAL OF PHARMACEUTICAL SCIENCES ISSN 2249- 1023 A Review on Synthetic Protocols of Pyridazine and Pyridazone Analogues

Vikas Jakhmola 1,2, Sunil Jawla 1, Prianshu Tangri 1,2, Ravinesh Mishra 3*

1 Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University, Gangoh, Saharanpur-247341, Uttar Pradesh, India

2 Department of Pharmacy, GRD (PG) IMT, Dehradun-248001, Uttarakhand, India

3 School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences and Technology, Baddi (Solan)-173205, Himachal Pradesh, India

Address for Correspondance ABSTRACT: Several methods for syntheses are available in literatures which involve conventional Ravinesh Mihra, synthesis methods. Most synthesis of pyridazine is based on the addition of hydrazine or its derivative to an [email protected] appropriately 1,4-disubstituted carbon chain. As part of our program aimed at utilizing β-aroylpropionic acid om derivatives containing the different aromatic moiety as starting materials react with different hydrazine Keywords derivatives for the synthesis of pyridazine and pyridazinone derivatives, these reports of interesting biological Pyridazine; 4,5- activities prompted us to synthesize a new series of pyridazinones containing different other moieties to give Dihydropyridazin the corresponding pyridazinone. © 2015 iGlobal Research and Publishing Foundation. All rights reserved. -3(2H)-one; Synthetic Methods.

Pyridazines have not been investigated as thoroughly as the INTRODUCTION other isomeric diazines especially pyrimidine because they are not known to occur in nature and are not easily produced by nitrogen biochemical transformation. Since, some pyridazines The diazines are six membered ring containing two nitrogen have been found useful as growth inhibitors or medicinal atoms. Three isomeric diazines are theoretically possible and compounds; the literature has been expanding day by day. all of them are known.

Pyridazine has been assumed to be a planar molecule for N N N which two Kekule structures are given as mentioned. N Pyridazine is a resonance hybrid in which the greater N N contribution is made by the structure containing = N- 3 1,2-Diazine 1,3-Diazine 1,4-Diazine N=configuration . The 1,2 diazine systems that contain a carbonyl group in the ring are called pyridazinone. (Pyridazine) (Pyrimidine) (Pyrazine)

O 1 Knorr Coined the term pyridazine for 1,2 diazine ring system , N N however Fischer first prepared substituted pyridazines in 1886 H 2 & later on by Tauber in 1895. 4,5-Dihydropyridazin-3(2H)-one

Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 During last two decade numbers of pyridazines have been (A) Ring closure of acyclic compounds, synthesized due to variety of biological activities specially (B) Alteration and or Fusion with Other Heterocyclic Ring related to cardiovascular system. System, and (C) Substitution and Displacement on Pyridazinone System Properties of Pyridazine (A) Ring Closure of Acyclic Compounds Pyridazine being a pie electron deficient heteroaromatic i) 1,2-Dicarbonyl compounds: Compounds containing compound is a colorless liquid at room temperature with carboxylic group and an active methylene group on pyridine like odour & melting point of -8°C. condensation with 1,2-dicarbonyl group containing compounds in presence of hydrazine give substituted 7 Pyridazine is a weak base with boiling point 208°C. This pyridazinones . unusually high boiling point compared to benzene (80°C) indicates the involvement of some type of intermolecular R4 association and is attributed to the polariseability of N-N unit, O O OR R4 O N 4 which results in extensive dipolar association in the liquid . + + O N NH R3 H N R 2 R R1 R Pyridazine forms pyridazinium mono-cation with acids. It 1 2 3 R2 undergoes nucleophilic substitution with great difficulty; but Scheme 1 conversion into 1-oxide gives a means of preparing various Method 1 pyridazine substitution products5.

O O ii) Most of the compounds having 6-(alkylaminophenyl)-6- N + N + N N N PhCOOH N H2SO4 N N dimethylaminophenyl, and 6-(o-substituted phenyl)

HNO3 constituents are prepared by treatment of appropriate --keto 8 NO NH acid or --keto ester with hydrazine (Method 2). 2 2 R'' R' H N N R'' N Facile elimination of nitrogen can be used in conjugation with CO C CH2COOZ + O H NH Diels-Alder addition to construct aromatic rings. Pyridazine- 2 R R 3,6-dicarboxylate ester reacts with electron rich alkene to give R' Scheme 2 adducts that undergo subsequent elimination of nitrogen6. + ZOH Method 2 COOMe COOMe iii) Pyridazinone derivatives are also synthesized from Claisen condensation of levulinic acid with benzaldehyde followed by OMe MeO N N reaction with hydrazine hydrate9 (Method 3). + H C Me N 2 2 R1 R (R ) N N 2 4 2 NMe Piperidine 2 + CH -CO-CH-C-COOH 3 Toluene COOMe COOMe COOMe CHO p-(Substituted) (Substiuted)-B-methyl NMe benzaldehyde levulinic acid 2 R -MeOH 2 COOH R R2 4 - N R4 2 NH2NH2 H O O (R4)2 2 R1 O COOMe N N H R1

R2 R4 Methods of Preparation of Pyridazines/Pyridazinones MnO2 R1 THF, O N N The methods for the preparing pyridazine and pyridazinones H can be grouped into three main categories: Scheme 3 Method 3

Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 iv) The reaction between diarylglyoxal monohydrazone (1), vii) Synthesis of new series of 4,5-dihydro-3(2H)- isocyanides (2), aldehydes (3), affords a series of 3(2H)- pyridazinones has been carried out according to Method 7. pyridazinones10 in very simple manner (Mehod 4). The Ring closure of the requisite -keto acid is readily intermediate Ugi-four component condensation products are accomplished in high yield with hydrazine in refluxing never observed due to their tendency to cyclize when the less ethanol13. reactive cyclopentanone is used instead of aldehyde. Ph-NCO MeOOC R + MeOOC NO2 R Satisfactory yield is obtained for 3(2H)-pyridazinone with the TEA 4 5 N O preformed azine. 6

HOOC R O OH O R' 10% NaOH C/Pd Ph NNH 2 X C HOOC R o-C6H11CN (2) N H CO N O 10% NaOH 8 R'-CHO (3) N HN 7 Ph O Ph Ph 1 O NH2NH2 R N N X = CN, COOC2H5 H Scheme 4 OH Method 4 Scheme 7 9 Method 7 Intermediate (8) is obtained through a two step sequence v) 6-Aryl-2,3,4,5-tetrahydro-3-pyridazinones can also be involving a 1,3-dipolar cycloaddition reaction between the obtained by dehydrocyclisation of various hydrazides formed nitric oxide generated from 4-nitrobutyric acid methyl ester by the reaction of appropriate methyl -aroyl propionate and (4) and the appropriate alkene (5) followed by reductive ring 11 hydrazine hydrate in presence of sodium acetate (Method 5). opening of the formed cycloproduct. viii) A number of 4,6-disubstituted pyridazinone analogues14 Appropriate (CH2CO)2O Aromatic R OH AlCl have been synthesized since the original synthesis of Compound 3 O O Minaprine (psychotropic drug with pyridazine nucleus) is Dimethyl sulphate applicable to a great number of such types of analogues, which R O R NHNH starts with the use of acetophenone (Method 8). The first step 1 2 R OMe N N O O of the synthesis involves a ketolization reaction between

R1 R = Aryl acetophenone (10) and pyruvic acid (11) to give -methyl-- R = H, Ph Scheme 5 1 Method 5 benzollactic acid (12). The cyclocondensation of the - ketoacids with hydrazine gives the vi) Pyridazinone ring system fused with benzoselenazine hydroxydihydropyridazinones (13). Tertiary alcoholic group is moiety is synthesized from aminophenyl-3-methyl then easily dehydrated in an acidic medium giving oxybutyrate12. It is treated with potassium selenocyanate in pyridazinone (14). acetic acid and bromine. The resultant cyanate is hydrolyzed O CH3 O with sodium sulfide to give aminoselenol; which is then O OH OH KOH cyclised to the selenazine with chloroacetyl chloride. Reaction + CH3 HO O with alcoholic hydrazine gives the desired compound (Method O CH3 12 6). 10 11

NH NH COOEt COOEt 2 2 CH OH H C H3C 3 3 CH + 3 HSe H KSeCN, Br2 O O ClCH2COCl O O N N N N H N H N 2 2 H H COOEt H3C O 14 13 H C 3 Se NH Scheme 8 N Method 8 Se NH2NH2 O O N H ix) Saturated 1,4-diketones have also been used for the O N H 1,4-Benzoselenazinyl pyridazine synthesis. The intermediate dihydro compound 15 Scheme 6 pyridazinone may be oxidized by chromium trioxide in acetic acid Method 6 (Method 9). 67

Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 iii) Pyridazinone can be synthesized in an unusual way from 18 R O R N R N the reaction of glyoxalic acid and tetralone as illustrated in O NH [O] N + NH NH 2 2 Method 13. R R R Method 9 Glyoxalic acid Zn x) Bis-pyridazinone derivatives can be synthesized through the OH- Acetic acid 16 formation of Mannich bases . 1,4-diacetyl benzene on O O COOH treatment with formaldehyde and dimethylamine gets Tetralone converted to Mannich bases. These undergo elimination- NH NH addition with cyanide to give the dinitrile derivative; which on 2 2 hydrolysis gives corresponding diacid. Cyclocondensation of O COOH N diacid with hydrazine hydrate gives bis-pyridazinone N O H compound. m-Nitrobenzene NHCH3 CN sulphonate O O COCH N 3 N O H NHMe2 KCN Scheme 10 MeOH HCHO Method 13 COCH 3 O O iv) Pyridazinone derivatives can also be synthesized by

NHCH3 CN Friedel Crafts acylation of substituted benzene with dimethyl O maleic anhydride which gives lactol19. Reduction of olefinic COOH NH center in lactol is accomplished with zinc and acetic acid. The O N crude reduction product is then treated with hydrazine, to get dihydropyridazinone. conc. HCl NH2NH2.H2O R O O O H3C N R O + O NH HO CH H C 3 COOH 3 H C Scheme 9 O O 3 Method 10 Lactol

(B) Alteration and/ or Fusion with Other Heterocyclic H3C CH3 Ring System NH2NH2 i) A common versatile method for the preparation of R O N N pyridazine diones consists of condensation of maleic acid H derivatives and their mono- and disubstituted analogues with 17 Scheme 11 hydrazines . Method 14 R R v) Pyridazino-indole derivatives are synthesized from the O O O O N O N RNHNH2 N + N reaction of p-alkoxy anilines and ethyl--methyl 20 R1 R2 R1 OH R2 OH acetoacetate (Method 15). These alkoxy indoles formed in R2 R1 first step are then formylated using DMF/POCl3 through Method 11 Vilsmeier-Haack reaction. Formyl indol carboxylates on ii) Treatment of aromatic -lactones of ,-dihalocinnamic boiling with hydrazine for 2-3 h gives respective pyridazino- acids with hydrazine also yield substituted pyridazinone. indole derivatives. OR O H O O OR O H O N + NH2NH2.HCl N H3C Ar H C COOEt N COOEt 3 H NH Cl Cl Ar 2 p- Alkoxy Cl aniline OR OR CHO NH2NH2 N Method 12 DMF/POCl3 NH N N COOEt H H O

Method 15 Scheme 12 68

Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 (C) Substitution and Displacement on Pyridazinone (16), which on cyclisation with hydrazine gives pyridazinone System (17) (Method 19).

H3C CH3 H C i) Most commonly used method for synthesis of 3-(2- 3 NaH / DMF substituted)- pyridazinones involves N-alkylation of 3,6- N COOH N COOH CH3I N dialkoxy pyridazinones21. N O O 16 15 CH3 H3C CH3 OR N O N N- alkylation N N NH NH 2 2 N O N N N OR OR H 17 Method 16 Method 19 Scheme 15 ii) Pyridazinone derivatives having benzoxazine substitution iv) A series of 5-aryliendene pyridazinone substituted in 2- on it can be synthesized by using Thyes method22. In this position by Mannich bases have also been synthesized24. method, keto acids are prepared by Friedel-Crafts acylation of Introduction of aryl or heteroaryl piperazino group on 3,4-dihydro-1,4-(2H)-benzoxazine with succinic anhydride different pharmacophores has been of considerable interest for and aluminum chloride. The resultant keto acid is heated with medicinal compounds. Synthetic procedure involves refluxing hydrazine hydrate to form 1,4-benzoxazinyl pyridazin-3-one. a solution of formaldehyde, pyridazinone and arylpiperazine O O R Succinic anhydride 1 in ethanol for 12 h and evaporating the mixture under reduced AlCl X pressure. N 3 N H3C R R O N NH

NH NH O 2 2 CF3

R1 O R1 R HN N 1 N

N + HCHO N R N CH2CH2Cl N O H C H 3 N

1,4-benzoxazinylpyridazin-3-one N CH2CH2 N N MethodScheme 17 13 O CF 3

R Scheme 16 In another method, chloroacetyl chloride is used with 1 Method 20 appropriate o-aminophenol to give desired benzoxazine. These v) Spirocyclopentaneindolepyridazinone is synthesized from compounds are then acylated by using succinic anhydride to cyclopentane carboxylic acid-2-phenylhydrazide (18). Base give oxobutyric acid. Cyclization with hydrazine gives induced rearrangement of this product results in formation of pyridazinones. spirocyclopentaneindol-2-one (19). The dihydropyridazinone OH O ClCH COCl 2 ring is then synthesized by using succinic anhydride in AlCl-

N R O N 3/DMF according to Thyes method. Finally cyclization with H 1 R N-substituted 1 hydrazine hydrate results into pyridazinone derivative (21) o-amino phenol Succinic anhydride with spirocyclic substitution in it. AlCl3 O O H O R N AlCl3 R 2 N CaH2 2 H O NH2NH2 X N DMF N H 18 N 19 O N R1 R1 N O H O O 1,4-benzoxazinylpyridazin-3-one HOOC Method 18 NH2NH2 . H2O Scheme 14 O HN N N O 20 H iii) Synthesis of pyridazinones substituted with imidazolyl N 23 H moiety is accomplished with the formation of 4-(1H- Scheme 17 21 imidazol-1-yl)--methyl--oxobenzene butanoic acid (15) or Method 21 69

Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 Another method can be used to synthesize similar compounds electronic data processing. as given below in the Method 22.

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