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Medicinal Chemistry
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Novel Route for Synthesis of Antihypertensive Activity of Tetrazole Analogues as a Carbamate and Urea Derivatives

Ramakrishna Vellalacheruvu1,2*, Sai Leela R3 and Ravindranath LK4

1Department of Chemistry, SK University, Anantapur, Andhra Pradesh, India

2GVK Bio Science Pvt. Ltd., IDA Nacharam, Secunderabad, Telangana, India

3College of Pharmacy, SK University, Anantapur, Andhra Pradesh, India

4Chemistry Department, SK University, Andhra Pradesh, India

*Corresponding Author:
Ramakrishna Vellalacheruvu
Department of Chemistry, SK University
Anantapur, Andhra Pradesh, India
Tel: 9493268448
E-mail: [email protected]

Received Date: August 21, 2017 Accepted Date: August 28, 2017 Published Date:August 31, 2017

Citation: Ramakrishna V, Sai Leela R, Ravindranath LK (2017) Novel Route for Synthesis of Antihypertensive Activity of Tetrazole Analogues as a Carbamate and Urea Derivatives. Med Chem (Los Angeles) 7: 239-246. doi: 10.4172/2161- 0444.1000463

Copyright: ©2017 Ramakrishna V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

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.

Keywords

Tetrazolidine; Diphenyl phosphoryl azide; [3+2] Cycloaddition reaction; Curties re-arrangement; Combi- flash chromatography

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 1H NMR.

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 and antibacterial [2], corrosion inhibitor [3], antiinflammatory [4], anticancer [5,7], 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 bioavailability and prolonging biological action and also avoid 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 AT1 and AT2 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 anti-hypertension drugs were described in Figure 1.

medicinal-chemistry-inhibitors

Figure 1: List of ACE inhibitors as an anti-hypertensive drugs.

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.

medicinal-chemistry-Metabolically

Figure 2: Metabolically bioisostere for carboxy and amide functional groups.

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.

medicinal-chemistry-Cephalosporin

Figure 3: Generation of Cephalosporin Antibiotics.

Dave et al. 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.

image

Subramanian et al. developed a novel route for terazole analgous of Cl-Amidines and F- Amidines.

As a part of our research work, we synthesized a high potential tetrazolidine analogous were synthesized as a urea and carbamate 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, I2). 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. 1HNMR, 13CNMR spectra were recorded with a Bruker spectrometer operating at 400 MHz used as a trimethylsilane as a reference and values were recorded in ppm. The progress of reaction was monitored using TLC system and I2 spray and KMnO4 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.

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.

medicinal-chemistry-compounds

Scheme 1: The detailed scheme of prepared compounds.

medicinal-chemistry-mechanism

Figure 4: The detailed reaction mechanism for step 4.

Step-1: 8-(benzyloxy)quinoline-5-carboxylic acid (2).

Step-2: 8-(benzyloxy)-N-(4-(trifluoromethyl)phenyl)quinoline- 5-carboxamide (3).

Step-3: (E)-8-(benzyloxy)-N-(4-(trifluoromethyl)phenyl) quinoline-5-carbimidoyl chloride (4).

Step-4: 8-(benzyloxy)-5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinoline (5).

Step-5: 5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-ol (6).

Step-6: Ethyl 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol- 5-yl)quinolin-8-yl)oxy)acetate (7).

Step 7: 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)acetic acid (8).

Step 8: 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)acetyl azide (9).

Step 9: Substituted (((5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinolin-8-yl)oxy)methyl)carbamate (10a-e).

Step 10: substituted-3-(((5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinolin-8-yl)oxy)methyl)urea (11a-e).

Reaction conditions

Step 1: CrO3/H2SO4, 0°C, 3 h, Step 2: HBTU /DIPEA (3 eq), DMF. Rt, 16 h Step 3: POCl3/DMF (cat), 0°C-50°C,3 h Step 4: NaN3 / DMF, 80°C, 4 h Step 5: 10% Palladium on Carbon, H2/ 90 psi Step 6: Ethyl Bromo Acetate, NaH, 0°C- RT, 6 h Step 7: LiOH, THF/H2O (1:4), 16 h Step 8 : DPPA / Toluene, 0°C, 8 h Step 9: R-OH, Toluene, 90°C, 5 h, Sealed tube.

Reaction mechanism

Step 1: 8-(benzyloxy)quinoline-5-carboxylic acid (2):

image

Zones Reagent: In a 1 lit 3 neck round bottom flask fitted with mechanical stirrer, CrO3 (28 g, 0.285 mol) was dissolve in water (50 mL) and cooled to 0°C for 10 min. Then added H2SO4 (5.5 M, 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 × 250 mL). The reaction mixture was filtered on cellite bed. The organic layer were separated and dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give black crude product. The crude was purified by column chromatography (100-200 mesh silica, Eluent: Pure EtOAc) isolated 8-(benzyloxy)quinoline-5-carboxylic acid (15 g, Yield: 57%) as a white solid. M.P. 282-285°C. IR (KBr, cm–1): 3400, 3010, 1710, 1580, 1440, 770, 655. 1HNMR (d6-DMSO, 400 mHz): 4.9 (s, 1H), 7.35- 7.5 (m, 5H), 7.8 (t, 1H), 8.4 (d, 1H), 8.9 (d, 1H), 9.5 (d, 1H), 10.2 (brs, 1H).

Step 2: 8-(benzyloxy)-N-(4-(trifluoromethyl)phenyl)quinoline- 5-carboxamide (3):

image

To a mixture of 8-(benzyloxy)quinoline-5-carboxylic acid (15 g, 0.053 mol), 4-(trifluoromethyl) aniline (8.6 g, 0.053 mol) in DMF (100 mL) was added Di-isopropyl ethyl amine (DIPEA) (25 mL, 0.159 mol) and cooled to 0°C. Then HBTU (22 g, 0.06 mol) was added and stirred at room temperature for 16 h. The progress of reaction was monitored by TLC and iodine strain. After completion, reaction mixture was poured in ice cold water (300 mL) and extracted with EtOAc (3 × 300 mL). The organic layer was separated and washed with brine solution (100 mL). The organic layer was collected and dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give crude residue. The crude product was purified by Combi-flash column chromatography (230- 400 meshsilica, Eluent: 10% MeOH-CHCl3) isolated 8-(benzyloxy)-N- (4-(trifluoromethyl) phenyl) quinoline-5-carboxamide (3) (16 g, yield: 72%) as a white solid. M.p: 352-355°C. IR (KBr, cm–1): 3410, 3020, 1700, 1610, 1320, 1420, 780, 685. 1HNMR (d6-DMSO, 400 mHz): 5.1 (s, 2H), 7.2 (d, 1H), 7.38-7.5 (m, 5H), 7.6 (d, 2H), 7.63 (d, 2H), 7.83 (t, 1H), 8.8 (br, 2H), 9.5 (d, 1H).

Step 3: (E)-8-(benzyloxy)-N-(4-(trifluoromethyl)phenyl) quinoline-5-carbimidoyl chloride (4):

image

8-(benzyloxy)-N-(4-(trifluoromethyl)phenyl)quinoline-5- carboxamide (3) (15 g, 0.035 mol) in POCl3 (150 mL) was cooled to 0°C. Then added DMF (cat, 1 mL) drop wise and stirred at room temperature for 1 h. The reaction mixture was heated at 60°C for 3 h. 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 × 100 ml) to give crude product. The crude was carried to next step without further purification. This compound data was not analyzed.

Step 4: 8-(benzyloxy)-5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinoline (5):

image

(E)-8-(benzyloxy)-N-(4-(trifluoromethyl)phenyl)quinoline-5- carbimidoyl chloride (4) (15 g, 0.035 mol) in dry DMF (70 mL) was cooled to 0°C. Then sodium azide (3 eq) was added portionwise and stirred at room temperature for 1 h. After that, Reaction mixture was heated at 80°C for 4 h. The progress of reaction was monitored by TLC.

After completion, reaction mixture was cooled to 0°C and poured in ice cold water (200 mL) and basified up to PH-8 with sat aq NaHCO3 sol. The aqueous layer was extracted with EtOAc (3 × 100 mL). The organic layer were collected and dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give crude product. The crude was purified by column chromatography (100-200 mesh silica, Eluent: 50% EtOAc-Pet Ether) isolated 8-(benzyloxy)-5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5-yl) quinoline (5) (8 g, Yield : 50%) as a pale yellow solid. M.p: 280-282°C. IR (KBr, cm–1): 3010, 1550, 1510, 820, 655 1HNMR (d6-DMSO, 400 mHz): 5.10 (s, 2H), 7.1 (d, 1H), 7.4-7.68 (m, 11H), 8.4 (d, 1H), 8.78 (d, 1H).

Step 5: 5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-ol (5):

image

8-(benzyloxy)-5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5- yl)quinoline (5) (8 g, 0.012 mol) in MeOH (100 mL) was added 10% palladium on carbon and TFA (10 mL) and hydrogenated at 80 Psi using parr shaker for 5 h at room temperature. The progress of reaction was monitored by TLC. After completion, Reaction mixture was filtered on cellite bed and washed with MeOH (2 × 50 mL). The organic layer was collected and evaporated under vacuum to give crude residue. The residue was purified by combi-flash column chromatography isolated 5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5-yl) quinolin-8-ol (6) (5.5 g, Yield: 88%). as a white solid. M.p:310-315°C. IR (KBr, cm–1): 3300, 3040, 1580, 1425, 1150,760, 691, 1HNMR (d6-DMSO, 400 mHz): 7.2 (d, 1H), 7.5-7.62 (m, 5H), 7.8 (d, 1H), 8.4(d, 1H), 8.88 (d, 1H). 10.1 (brs, 1H).

Step 6: Ethyl 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol- 5-yl)quinolin-8-yl)oxy)acetate (7):

image

To a solution 5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5- yl)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 Na2CO3 up to PH-8 and extracted with EtOAc (2 × 100 mL). The organic layer were separated and washed with brine (25 mL), and dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give give crude product. The crude was purified by column chromatography (100-200 mesh silica, Eluent: 60% EtOAc- Pet ether) isolated ethyl 2-((5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5-yl)quinolin-8-yl) oxy)acetate (4 g, Yield: 64%) as a semi brown colour liquid. M.p::255- 258°C. IR (KBr, cm–1): 3040, 1640, 1560, 1440, 1130, 780, 698, 1HNMR (d6-DMSO, 400 mHz) : 1.4 (t, 3H), 3.8 (q, 2H), 4.8 (s, 2H), 7.23 (d, 1H), 7.5-7.62 (m, 5H), 7.75 (d, 1H), 8.39 (d, 1H), 8.7(d, 1H).

Step 7: 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)acetic acid (8):

image

Ethyl 2-((5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)acetate (8) (4 g, 0.009 mol) in THF/H2O (40 mL/10 mL, 4:1) was added LiOH (4 eq) and stirred at room temperature for 16 h. The progress of reaction was monitored by TLC. After completion, reaction mixture was poured in ice cold water (100 mL) and acidified with aq NaHSO3 (100 mL) up to PH-4 and extracted with EtOAc (3 × 100 mL). The organic layer were collected and dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give crude product. The crude was purified by column chromatography (100-200 mesh silica, Eluent: 80% EtOAc- Pet ether) isolated 2-((5-(1-(4-(trifluoromethyl) phenyl)- 1H-tetrazol-5-yl)quinolin-8-yl)oxy)acetic acid (3.5, Yield: 93%) as a white solid. M.p: 285-288°C. IR (KBr, cm–1): 3500, 3030, 1690, 1560, 1440, 760, 610, 1HNMR (d6-DMSO, 400 mHz): 4.8 (s, 2H), 7.3 (d, 1H), 7.5-7.65 (m, 5H), 7.78 (d, 1H), 8.38 (d, 1H), 8.8(d, 1H), 10.4 (brs, 1H).

Step 8: 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)acetyl azide (9):

image

To a solution of 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol- 5-yl)quinolin-8-yl)oxy) acetic acid (3.5 g, 0.008 mol) in toluene (35 mL) was added DPPA (2.25 mL, 0.014 mol) at 0°C and stirred at room temperature for 8 h. The progress of reaction was monitored by TLC. After completion, reaction mixture was evaporated under vacuum to give crude residue. The crude residue was co-distilled with Toluene (2 × 30 mL) isolated 2-((5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5- yl)quinolin-8-yl)oxy)acetyl azide (4.5 g) as a liquid. The crude residue was carried to next step without further purification.

Step 9: Substituted (((5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinolin-8-yl)oxy)methyl)carbamate (10):

image

To a solution of 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol- 5-yl)quinolin-8-yl)oxy)acetyl azide (9) (250 mg, 0.568 mmol) in Dry toluene (10 mL) was added TEA (1.7 mmol, 3 eq), Alcohol (1.1 eq) and heated at 100°C for 5 h in sealed tube (50 mL). The progress of reaction was monitored by TLC. After completion, reaction was evaporated under vacuum to give crude product. The crude was purified by Combi-flash column chromatography (100-200 mesh silica, Eluent: 70% EtOAc-Pet ether), isolated substituted (((5-(1-(4-(trifluoromethyl) phenyl)-1H-tetrazol-5-yl)quino lin-8-yl)oxy)methyl)carbamate 10 (ae). The list of carbonate derivatives was given in Table 1.

Compounds (10a-f) R Reaction Time Yield
10 a Me 5 h 40%
10 b Et 8 h 55%
10 c tBu 16 h 60%
10 d Benzyl 10 h 50%
10 e MeO-C6H4-CH2 6 h 65%

Table 1: Summary data for N-carbamate derivatives.

Methyl(((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)methyl) carbamate (10 a):

image

M.p: 280-283°C. IR (KBr, cm–1): 3450, 3030, 1645, 1350,780, 645, 1HNMR (d6-DMSO, 400 mHz): 3.5(s, 2H), 5.5(s, 2H), 7.2 (d, 1H), 7.5- 7.64 (m, 5H), 8.1 (m, 3H), 8.4(d, 1H), 8.8(d, 1H). 13CNMR (d6-DMSO, 400 mHz): 51, 75, 108, 122, 123, 124.5, 125,131,132, 135, 139, 149, 155, 157, 163.

Ethyl (((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)methyl) carbamate (10 b):

image

M.p: 290-293°C. IR (KBr, cm–1): 3450, 3035, 1650, 1350,785, 650, 1HNMR (d6-DMSO, 400 mHz): 1.25 (t, 3H), 4.2 (q, 2H), 5.4 (s, 2H), 7.2 (d, 1H) 7.55-7.63 (m, 5H), 7.9 (m, 2H), 8.38 (d, 1H), 8.85 (d, 1H). 13CNMR (d6-DMSO, 400 mHz): 15, 62, 77, 107.5, 122, 123, 124, 125, 131, 132, 135, 140, 150, 155, 156, 164.

Tert-butyl(((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)methyl) carbamate (10 c):

image

M.P.: 250-253°C, IR (KBr, cm–1):.3470, 3040, 1670, 1380,770, 640. 1HNMR (d6-DMSO, 400 mHz): 1.5 (s, 9H), 5.5 (s, 2H), 7.18 (d, 1H) 7.55-7.63 (m, 5H), 7.8 (m, 2H), 8.37 (d, 1H), 8.83(d, 1H). 13CNMR (d6- DMSO, 400 mHz): 30, 76, 79, 107, 121, 122.8, 124.9, 131, 132, 136, 139, 148, 155, 156, 163.8.

Benzyl (((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)methyl) carbamate (10 d):

image

M.p: 300-303°C. IR (KBr, cm–1): 3490, 3030, 1650, 1380,780, 660. 1HNMR (d6-DMSO, 400 mHz): 5.1 (s, 2H), 5.6 (s, 2H), 7.2 (d, 1H) 7.55- 7.63 (m, 10 H), 7.85 (m, 2H), 8.39 (d, 1H), 8.85(d, 1H). 13CNMR (d6- DMSO, 400 mHz): 68, 78, 108, 122, 123, 124, 124.5, 125.3, 127, 127.6, 129, 131, 132, 135.2, 136, 139, 148, 155, 156, 163.

4-methoxybenzyl (((5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinolin-8-yl)oxy)methyl)carbamate (10 e)

image

M.P.320-323°C, IR (KBr, cm–1): 3460, 3050, 1640, 1370,785, 665. 1HNMR (d6-DMSO, 400 mHz): 3.83 (s, 3H), 4.9 (s, 2H), 5.65 (s, 2H), 6.9-7.1 (m, 5H), 7.55-7.62 (m, 5 H), 7.85 (m, 2H), 8.38 (d, 1H), 8.87 (d, 1H). 13CNMR (d6-DMSO, 400 mHz): 56, 67, 76, 108, 115, 122, 123, 123.8, 124, 124.1, 125.3, 128, 129,130, 131.9, 132, 135.2, 139, 149, 154, 156, 158, 164.

Step 10: 3-(((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)methyl) urea derivative (11):

image

To a solution of 2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol- 5-yl)quinolin-8-yl)oxy)acetyl azide (9) (250 mg, 0.568 mmol) in Dry toluene (10 mL) was added Amine (1.3 eq) and heated at 100°C for 5 h in sealed tube (50 mL). The progress of reaction was monitored by TLC. After completion, reaction was evaporated under vacuum to give crude product. The crude was purified by Combi-flash column chromatography (100-200 mesh silica, Eluent: (5-10% MeOH-CHCl3), isolated 1-(((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl) quinolin-8-yl)oxy)methyl) urea derivatives 11 (a-e). The list of urea derivatives was mentioned in Table 2.

Compounds 11(a-e) 11a 11b 11c 11d 11e
R image image image image P-MeO-C6H4-NH2
Reaction Time 6 h 10 h 8 h 6 h 3 h
Yield 60 % 40 % 55 % 45 % 64 %

Table 2: The summary of urea derivatives 11(a-e).

1,1-diethyl-3-(((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol-5- yl)quinolin-8-yl)oxy)methyl) urea (11 a): IR (KBr, cm–1):

image

White solid, IR (KBr, cm–1): 3410, 3010, 1730, 1655, 1450, 1320,780, 650,.1HNMR (d6-DMSO, 400 mHz): 1.5 (t, 6H), 3.8 (q, 4H), 5.4 (s, 2H), 7.15 (d, 1H), 7.5-7.6 (m, 5H), 7.8 (m, 2H), 8.38 (d, 1H), 8.8(d, 1H). 13CNMR (d6-DMSO, 400 mHz): 15, 45, 78, 108, 122, 123, 124, 124.5, 125, 131, 132, 135, 139, 149,155,157, 164.

11,1-diisopropyl-3-(((5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinolin-8-yl)oxy) methyl)urea (11 b): IR (KBr, cm–1):

image

Off white colour solid, IR (KBr, cm–1): 3430, 3020, 1720, 1645, 1440, 1330,760, 640.1HNMR (d6-DMSO, 400 mHz): 1.4 (d, 12H), 3.8 (q, 2H),5.6 (s, 2H), 7.1 (d, 1H), 7.5-7.6 (m, 5H), 7.8 (m, 2H), 8.4 (d, 1H), 8.83(d, 1H). 13CNMR (d6-DMSO, 400 mHz): 21, 55, 77, 107, 121, 123, 124, 124.5, 131, 132, 133, 135, 139, 148, 154, 158, 165.

1-(tert-butyl)-3-(((5-(1-(4-(trifluoromethyl)phenyl)-1H-tetrazol- 5-yl)quinolin-8-yl)oxy) methyl) urea (11 c): IR (KBr, cm–1):

image

White colour solid, IR (KBr, cm–1): 3460, 3040, 1650, 1460, 1380, 680, 620.1HNMR (d6-DMSO, 400 mHz): 1.5 (s, 9H), 5.68 (s, 2H), 7.15 (d, 1H), 7.5-7.6 (m, 5H), 7.8 (m, 2H), 8.1 (brs, 1H), 8.43 (d, 1H), 8.84(d, 1H). 13CNMR (d6-DMSO, 400 mHz): 30, 58, 76, 108, 122, 123, 124, 124.5, 131.8, 132, 133, 135, 139, 146, 155, 157, 164.

1-Cyclopropyl-3-(((5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinolin-8-yl)oxy)methyl)urea (11 d): IR (KBr, cm–1):

Pale yellow colour solid, IR (KBr, cm–1): 3510, 3430, 3040, 1650, 1460, 1340, 690, 550.1HNMR (d6-DMSO, 400 mHz): 0.9 (t, 2H), 1.1 (t, 2H), 2.5 (m, 1H), 5.7 (s, 2H), 3.8 (brs, 1H), 7.15 (d, 1H), 7.5-7.6 (m, 5H), 7.81 (m, 2H), 8.3 (brs, 1H), 8.4 (d, 1H), 8.80(d, 1H). 13CNMR (d6- DMSO, 400 mHz): 8, 30, 76, 108, 122, 123.1, 123.5, 124, 125.3, 130.1, 132, 135, 139.1, 149, 155, 157, 164.

1-(4-methoxybenzyl)-3-(((5-(1-(4-(trifluoromethyl)phenyl)-1Htetrazol- 5-yl)quinolin-8-yl)oxy)methyl)urea (11 e):

image

White colour solid, IR (KBr, cm–1): 3540, 3430, 3030, 1640, 1440, 1350, 730. 1HNMR (d6-DMSO, 400 mHz): 3.6 (s, 3H), 4.2 (s, 2H), 5.7 (s, 2H), 6.8 (d, 2H), 7.1 (d, 1H), 7.25 (d, 2H), 7.5-7.6 2(m, 5H), 7.83 (m, 2H), 8.25 (brs, 1H), 8.41 (d, 1H), 8.84(d, 1H). 13CNMR (d6-DMSO, 400 mHz): 45, 56, 77, 107.5, 115, 121, 122, 123, 124, 130, 130.5, 130.8, 132.2, 135, 140, 149, 155, 157, 158, 163.

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 carbamate derivatives. We employed very easiest method for preparation of urea and carbamate derivatives and avoid side products. We are planning to these derivatives check for biological evolution. The biological evolution details will include next article.

Acknowledgements

I sincerely thank my guide, Dr. LK Ravindranath and Co-workers, Department of Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India and GVK Bio Sciences for providing laboratory and analytical facilities.

References

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