Ultrasound assisted synthesis of 2, 4-substituted 1, 5- benzothiazepine derivatives

A series of 15 novel derivatives of Synthesis of 2, 4-substituted 1, 5benzothiazepine 5(a–l) were synthesized in good yield from the key compound 1, 3-substituted-prop-2-en-1-one 3(a-l), called chalcone, with 2-aminothiophenol (0.01mol) and pinch of zirconium oxychloride and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. The 1,5benzothiazepine scaffold has several biological activity such as vasodilator, antiarrythmic antagonists of several G-protein coupled receptors such as cholecystokinin (CCK) receptor, antiulcer activity, anticonvulsant activity.


Introduction
Synthesis of nitrogen and sulphur containing heterocycles is of current interest because of their useful, broad spectrum biological activities. The heterocycle such as 1,5-benzothiazepine have gained attention of medicinal chemists due to their use as drugs and medicaments in a large number of diseases.
1,5-benzothiazepine derivatives are well known on account of their wide synthetic applications and biological/pharmaceutical values. The 1,5-benzothiazepine scaffold has been used as cardiovascular modulator 1 such as vasodilator 2,3 and antiarrythmic 4 antagonists of several G-protein coupled receptors such as cholecystokinin (CCK) receptor 5 , antiulcer activity 6 , spasmolytic activities 7-8 , ACE inhibitors 9 , the angiotensin II receptor (ACE) inhibitors 10 . Benzothiazepines are bioisosters of benzodiazepines. The recent succesful exploitation of 1,5-benzothiazepine type of compounds such as diltiaze, thiazepam, chlordiazepoxide, diazepam and chlobazam as potential CNS, cardiovascular and psychopharmacological agents, prompted us to synthesis a new class of potential 1,5-benzothiazepine with heteyl moiety like indole, alipatic and aromatic ketones.
As the process of drug discovery is very time consuming, tedious and expensive , therefore, the efforts are made to minimize the duration of reaction time, enhance the yield, minimize or avoid use of solvents, especially the hazardous solvents. The green chemistry tools such as Ultrsound synthesizer, solvent-free reactions are used so as to avoid pollution of surroundings.
Sono-chemistry is the application of ultrasound technique has undergone very intensive research and development in the last 15-20 years to carry out chemical transformation. Ultrasound offers potential for cleaner reactions called green protocol keeping in mind to protect environment clean and green through improved product yields and selectivity towards desired product, reduce the time of completion of reaction [11][12][13] and enhanced ease of product recovery.
Ultrasound-promoted synthesis has various advantages over conventional synthesis techniques such as reactions were carried at room temperature and require much less time for completion hence saves time and electricity, highly accelerated reaction rate, requires use of very less amount of solvents, shortened work-up procedure. practically good yield of product, simple instrument with control on reaction parameters, and most important is eco-friendly neat and clean synthetic protocol.
In this research work we are reporting the synthesis of 2, 4-substituted 1, 5-benzothiazepine 5(a-l) derivatives in excellent yield using eco-friendly, prompt and suitable ultrasound-assisted green chemistry protocol.

Chemistry
Herein, we are reporting the synthesis 2, 4-substituted 1, 5-benzothiazepine 5(a-l) as illustrated in  Step II involved synthesis of 2, 4-substituted 1, 5-benzothiazepine 5(a-l) when compounds 3(a-l) reacted with ortho-amino thiophenol using a pinch of zirconium oxychloride as a catalyst under ultrasound irradiation using solid probe type synthesizer at room temperature. Physical characterization data of were shown in Table2.

Step I: Synthesis of 1, 3-substituted-prop-2-en-1-one 14 3(a-l)
These chalcone analogues were prepared by stirring aldehyde (0.01mol.) and various ketones(0.01 mol.) in ethanol containing 10% NaOH in separate flasks. The reaction mixture was kept aside for 24 hrs and then it was poured on crushed ice and was acidified with dil. HCl. The crude product thus obtained was filtered, dried and recrystallized with ethanol.

3.2.2
Step II: Synthesis of 2, 4-substituted 1, 5-benzothiazepine 15,16,17 5(a-l) In a beaker, compound 16(a-l) (0.01 mol), 2-aminothiophenol (0.01mol 1.27ml) and pinch of zirconium oxychloride were taken in DMF (20 ml). The reaction mixture was kept inside the acoustic box having solid probe type Ultrasonic processor for about 1-2 hours at room temperature. After completion of the reaction (monitored by TLC), the mixture was poured into ice cold water.