A Review on Synthesis of Benzothiazine Analogues

 

Neethu Rajiv, Sreelakshmi. N, Jisni Rajan, Dr. Leena K. Pappachen*

Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham University, Amrita University, AIMS Health Sciences Campus, Kochi-682041, Kerala, India

 

ABSTRACT:

Scientific advances mainly involves the development of new and highly reactive compounds. Nitrogen and sulphur containing benzothiazines forms highly active heterocyclic agents. Benzothiazines are prominent class of heterocyclic compound. Many studies have been done in the development of benzothiazine analogues. Microwave assisted synthesis, regioselective techniques and other methods are also used for benzothiazine synthesis. Various methods have been developed for the synthesis of benzothiazine derivatives. Benzothiazines exhibits numerous therapeutic activities like anti-HIV, calcium antagonistic, anti-serotinin, analgesic, anti-mycobacterial anti-microbial, anti-oxidant, anti-rheumatic, anti-inflammatory, anti-hypertensive ,calcium channel blocker, anti-malarial, potassium channel opener, cardiovascular, anthelmintic, neuroprotective, aldose reductase  inhibitor, herbicidal, pesticidal etc. This has raised the necessity to explore novel benzothiazine derivatives which can significantly contribute to the development of therapeutically active agents. And the newer development of novel benzothiazines derivatives also involves the same characteristic features and also contribute various activities.

 

 

 

 

INTRODUCTION:

Benzothiazines possessing wide variety of  activities like anti-microbial^1,2, anti-oxidant³, anti-rheumatic⁴, anti-inflammatory^5,6, anti-hypertensive^7,8, calcium channel blocker⁹, neuromuscular, anti-malarial, anti-HIV, calcium antagonistic, HCV NS5B polymerase inhibitors¹⁰, anti-malarial¹¹, potassium channel opener^12,13, cardiovascular, anthelmintic, neuroprotective, aldosereductase inhibitor, herbicidal, pesticidal, anti-serotinin, analgesic, anti-mycobacterial, N-methyl-D-aspartate receptor antagonist¹⁴ and calmodulin antagonistic⁹ activities etc. Heteroaromatic six membered rings having one nitrogen and sulphur atoms are called thiazines.

 

Thiazine ring fused with benzene ring system called benzothiazine. Its IUPAC name is 2, 3-dihydro-1, 4-benzothiazine having molecular formula C₅H₉NS and molecular weight 165.22. It is a slightly yellow diamond shaped plate or rhombic leaflets having acrid taste and garlic like odour. It is soluble in benzene, ether, DMSO and insoluble in water ¹⁵.

They exist in different isomeric forms:

A) 1, 2-benzothiazine

B) 1, 3-benzothiazine

C) 1, 4- benzothiazine

 

Heterocyclic chemistry consists of various nitrogen and sulphur containing compounds. Based on the substituent which is attached to the specific N and S forming the specific benzothiazine derivative. There are three isomers of benzothiazine, among these 1,4-benzothiazine is more active. 1, 4-Benzothiazines represents a group of medicinally important heterocyclic compounds which are widely used in drug design. Phenothiazine having anti-psychotic activity owed by its 1, 4-benzothiazine pharmacophore. It is also the basic moiety of various dyestuff, photographic developer, UV light absorber and anti-oxidant agents¹⁶. 1, 2-benzothiazines exhibit anti-inflammatory, anti-microbial, CNS depressant, anti-depressant activities. In this review, the broad spectrum activity of benzothiazine analogs are revealed in case of agrochemical and pharmaceutical industries. The selective COX 2 inhibitors like piroxicam, meloxicam, ampiroxicam possess benzothiazine nucleus which are used as NSAIDS.

 

Synthesis of benzothiazine derivative.:

Scheme 1: Ultrasonicator assisted synthesis:

1-(3-methyl-4H-1, 4-benzothiazin-2-yl)ethanone are prepared by reacting 2-aminobenzenethiols and 1,3-dicarbonyls in presence of a biocatalyst baker’s yeast, after the reaction mixture is sonicated at 20 KHz¹⁷.

 

 

Scheme 2:

2-aminothiophenol reacts with furan-2,5-dione to form 2H,4H-2-hydrazino-carbonyl methyl-3-oxo-1,4-benzothiazine.This is treated with acetyl acetone using ultrasonicator for 10 min to form 2H,4H-2-[3,5-dimethyl 4(substituted)phenyl azo pyrazole-1-yl]carbonyl methyl-3-oxo-1,4-benzothiazine derivative¹⁸.

 

 

Scheme 3: Microwave assisted synthesis:

4H-1,4-benzothiazine is synthesized by condensation of 2-aminobenzenethiol and betaketoester/betadiketones using basic alumina as solid support. Then it is irradiated in microwave at 540 W¹⁸.

 

 

Scheme 4:

4-aryl-8-arylidene-2-imino-6(dihydro-4H,7H-(3,1) benzothiazines was synthesized from Cyclohexanone and an aromatic aldehyde in the presence of NaOH and CH3OH to form 2,6-diarylidene Cyclohexanone and this product is again treated with thiourea in presence of KOH under microwave irradiation at a power of 80-100W and temperature 120 +/_ 5^oC for 10-12 mnts.

 

 

Scheme 5 From ring expansion reaction of benzothiazoline:

Monika et. al reported the synthesis of benzothiazoline from O-aminothiophenol undergo ring expansion reaction with the help of sulfonyl chloride to form benzothiazine derivative^15,19.

 

 

Scheme 6. From alpha-halo carbonyl system

Monika et.al reported the synthesis of benzothiazine from O-aminothiophenoland alpha-halocarbonyl system^15,20.

 

 

Scheme7 From alpha, beta- unsaturated acids and esters.

Monika et.al reported the synthesis of benzothiazine derivative from alpha,beta unsaturated acids and esters with O-aminothiophenol under 165-170^Oc temperature^15,21.

 

 

Scheme 8 From maleic anhydride:

Monika et.al reported the synthesis of benzothiazine prepared from the reaction of O-aminothiophenol with maleic anhydride diethyl ether, then an intermediate O-mercaptomaleanellic acid is formed and by nucleophilic anhydride ring opening cyclization providing the formation of 1,4-benzothiazine-2-acetic acid^15,22.

 

 

Scheme 9 From alpha cyano, alphaalkoxy carbonyl epoxides:

Monika et.al reported the synthesis of 1,4-benzothiazine from O-aminothiophenol and alpha cyano, alphaalkoxy carbonyl epoxides to form corresponding benzothiazine analogue^15,23.

Scheme 10:

1-(3-methyl-4H-1,4-benzothiazin-2yl) ethanone is synthesized by direct condensation of pentan-2,4-dione with o-aminothiophenol in the presence of ethanol for 4hours²⁴.

 

 

Scheme 11:

An excellent yielding method was developed for the preparation of 3-methyl-4H -benzo[b][1,4]thiazine-2- carboxylates. for the preparation alkyl acetoacetates are reacted with 2,2’-disulfanediyldianiline in the presence of triethylamine as catalyst²⁵.

 

 

Scheme 12:

2,3-disubstituted -1,4 –benzothiazines was obtained in high yields by the oxidative cyclocondensation of 2-aminobenzenethiols and 1,3-dicarbonyls using hydrazine hydrate as catalyst²⁶.

 

 

Scheme 13:

Deshmukh reported the synthesis of 2-methyl -1,4-benzothiazin-3(1H)-one refluxing 2-aminothiophenol with methyl-2-chloropropionate in the presence of sodium hydroxide(33%)²⁷.

 

 

Scheme 14:

Mohammad saadouni reported the synthesis of 1,4-benzothiazine by adding epoxide in acetonitrile to 2-aminothiophenol .Then this mixture is refluxed for 25hours²³.

 

 

Scheme 15:

The 2-amino-5-chloro-3-(trifluromethyl)benzenethiol which is produced by the hydrolytic cleavage of 2-amino-6-chloro-4-(trifluromethyl)benzothiazole has undergone condensation and oxidative cyclization with beta diketone or beta keto ester to form 4H- 1,4-benzenethiazine derivatives²⁸.

 

 

CONCLUSION:

The review highlights that various methods have been reported for the synthesis of benzothiazine.2-aminothiophenol is the most popular starting material which is used for the formation of benzothiazine and its derivatives. They shows various biological activities like anti-inflammatory, anti-microbial, antioxidant, analgesic, neurotransmitter ,anti-malarial, cardiovascular, ATP sensitive potassium channel blocker, anti-HIV etc. Benzothiazines are now a day’s used for the development of newer drugs which having anti-inflammatory, anti-microbial and anti-hypertensive agents by researchers.

 

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