Novel route for Synthesis of Antihypertensive activity of Tetrazole analogues as a Carbamate and Urea Derivatives

The Novel route was developed for synthesis of high potential tetrazole carbamate and urea derivatives by using conventional methods. (trifluoromethyl)phenyl)quinoline-5-carboxamide (3) was converted into chloroamidine derivative by using POCl3 and DMF (cat), then treated with sodium azide by [3 + 2] cycloaddition to give 8-(benzyloxy)-5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5-yl) quinoline (5). The tetrazolidine compound was debenzylated, then Alkylation with Ethyl Bromo acetate and converted to acid (8) by hydrolysis with LiOH. The acid was converted to acid azide by using DPPA, and then Treated with Alcohols and Amine to give substituted Carbamates and urea derivatives by using Curtius rearrangement.


Introduction
Tetrazole analogues have a potential pharmacological activity in medicinal chemistry division. Several Active Pharmaceutical Drug Intermediates (API) of tetrazole derivatives played their role in pharmaceutical and agrochemical region. These compounds act as multidimensional biological active drug candidates such as inhibition of Angiotensin (AT1), Angiotensin (AT2) receptor (Hypertension) [1], antifungal & antibacterial [2], corrosion inhibitor [3], anti-inflammatory [4], anticancer [5], [6,7], antioxidant [6], antifungal, analgesic [8], Antiviral [9], protein arginine deiminase inhibitor [10], antimicrobial [11,12], Anti allergic, Dual Selective Serotonin And Nor Epinephrine Reuptake Inhibitors (SSNRIs) and HIV inhibitors. When Drug model designing, tetrazole nucleolus consider as a co-sister of carboxylic acid and amide derivatives. The pka value of tetrazole is correlated with amide and acid functional groups. The introduction of tetrazole ring in drug substrate prominently increases their bio-availability and prolonging biological action and also avoids acute toxicity of drug. In Analogue-Based Drug Discovery (ABDD), introduce tetrazole nucleolus as an important descriptor. Several research works is progress based on synthesis of tetrazole amino acid analogues, and nucleotide and nucleoside analogues instead of acid and amide functional group.
Many Tetrazole analogs were available for treatment of hypertension, such as Losartan potassium, Valsartan, Irbesartan, Candesartan and Olmesartan medoxonil. These drugs played a vital role to inhibit Angiotensin converting enzyme. They block AT 1 & AT 2 receptors which is located in kidney, heart, vascular smooth muscle cells, brain, and adrenal glands. The Renin Angiotensin System (RAS) is a powerful regulator of Blood pressure. These drugs block Renin-Angiotensin System (RAS, enzyme) which is secretly produced in Kidney. Such few antihypertension drugs were described in Figure 1.
Tetrazole ring was widely used as a metabolically stable bioisostere for carboxy and amide functional groups in molecular design and synthesis of modified amino acids. Such analogs are described in Figure 2.
The generations of Cephalosporin Antibiotics played a vital role in diagnosis process. Huge research work has been done for development of these drug analogs shown in Figure 3.  Dave, C.G shah and coworkers synthesized 7, 9-Disubstituted-7H-tetrazolo [1,5-c] pyrrolo [3,2-e] pyrimidines and evaluated their biological activity. Below compound exhibited better activity than ampicillin against all tested culture. Venkataraman Subramanian and co worker developed a novel route for terazole analgous of Cl-Amidines and F-Amidines.

Organic and Medicinal Chemistry International Journal
As a part of our research work, we synthesized a high potential tetrazolidine analogous were synthesized as a urea and carbamates derivatives using conventional methods of cycloaddition reactions and curtius rearrangement reactions. Present method we avoid toxic and hazard reagents during synthesis of urea and carbamate derivatives.

Materials and Methods
All Amines and alcohols and Reagents collected from commercial sources (Aldrich, Alfa Aesar). THF and Toluene were thoroughly dried using sodum metal and benzophenone before conduct reaction. DMF was dried using CaH. Alcohols (EtOH, MeOH) were super dried using Grignard method (Mg, I 2 ). The Curtius rearrangement reactions were conducted in sealed tube. These derivatives were characterized by using Analytical methods like IR, NMR (400 m Hz, Bruker). The melting points were recorded using on a WRS-1A Digital Melting Point Apparatus without correction. Infrared spectra were taken using an AVATAR 370 FT-IR spectrometer. 1 HNMR, 13 CNMR spectra were recorded with a Bruker spectrometer operating at 400MHz used as a trimethylsilane as a reference and values were recorded in ppm. The progress of reaction was monitored using TLC system and I 2 spray and KMnO 4 TLC strain. The crude compounds were purified using column chromatography (100-200 mesh silica) and Combi-flash chromatography. The hydrogenation process was carried out using parr shaker.

Objective Of This Research
Present work is corresponding to develop novel synthetic route for preparation of the quinoline attached tetrazolidine urea and N-carbamate derivatives and characterized by IR and 1 HNMR.

Experimental Methods
In this research work, we prepared below compounds and mentioned in step wise manner. The detailed scheme was given in Scheme 1. The Reaction mechanism for step 4 was mentioned in Figure 4.

Reaction mechanism for
Step 2: Step 1: 8-(benzyloxy) quinoline-5-carboxylic acid (2): Step 1: 8-(benzyloxy)quinoline-5-carboxylic acid (2) Zones Reagent: In a 1 lit 3 neck round bottom flask fitted with mechanical stirrer, CrO 3 (28 g, 0.285 mol) was dissolve in water (50 mL) and cooled to 0 °C for 10 min. Then added H 2 SO 4 (5.5M, 130 mL, 0.3 eq) drop wise for 30 min at -5°C. The reaction mixture was stirred for 10 min. In Another RBF 8-(benzyloxy) quinoline-5-carbaldehyde (25 g, 0.09 mol) was dissolve in Acetone (250 mL) and cooled to 0°C. The above reagent (Zones reagent) was added drop wise for 1 h and stirred for 2 h. The progress of reaction was monitored by TLC. After completion, Reaction mixture was poured in ice cold water and stirred for 30 min. The reaction mixture was extracted with EtOAc (3 x 250 mL). The reaction mixture was filtered on cellite bed. The organic layer were separated and dried over anhydrous Na 2 SO 4 , filtered and evaporated under vacuum to give black crude product.

Step 3: (E)-8-(benzyloxy)-N-(4-(trifluoromethyl) phenyl) quinoline-5-carbimidoyl chloride (4):
Step 3: (3) (15 g, 0.035 mol) in POCl 3 (150 mL) was cooled to 0 °C. Then added DMF (cat, 1mL) drop wise and stirred at room temperature for 1h. The reaction mixture was heated at 60 °C for 3h. The progress of reaction was monitored by TLC. After completion, reaction mixture was cooled to room temperature. The POCl3 was evaporated under high vacuum to give crude residue. The residue was co-distilled with dry toluene (2 x 100 ml) to give crude product. The crude was carried to next step without further purification. This compound data was not analyzed.

OEt O
To a solution 5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5yl) quinolin-8-ol (6) (5 g, 0.014 mol), in DMF (50 mL) was cooled to 0°C. Then added sodium hydride (1.7 g, 0.042 mol, 3 eq) portion wise and stirred for 30 min. To that Ethyl bromo acetate (1.71 mL, 0.0154 mol) was added drop wise and stirred for 6 h at room temperature. The progress of reaction was monitored by TLC. After completion, reaction mixture was poured in ice cold water (100 mL) and basified with aq Na 2 CO 3 up to PH-8 and extracted with EtOAc (2 x 100 mL). The organic layer were separated and washed with brine (25 mL), and dried over anhydrous Na 2 SO 4 , filtered and evaporated under vacuum to give give crude product.

Conclusion
Present research work we have developed a novel route for synthesis of high potential pharmacological carbamate and urea derivatives using conventional and scalable route. We avoid by products in curtius rearrangement by using dry toluene and reactions were executed under argon atmosphere. We avoid hazard reagents like (phosgene and acid chloride methods) for preparation of urea and carbamates derivatives. We employed very easiest method for preparation of urea and carbamates derivatives and avoid side products. We are planning to these derivatives check for biological evolution. The biological evolution details will include next journal [13][14][15][16][17][18][19][20].