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COMPOSITIONS OF PARACETAMOL EMBEDDED [1, 2, 3]-TRIAZOLES AND THEIR METHOD OF PREPARATION THEREOF
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ORDINARY APPLICATION
Published
Filed on 13 November 2024
Abstract
7. ABSTRACT The present invention relates to the design and development of substituted Paracetamol derivatives by employing Click dipolar cycloaddition and Molecular hybridization Approach. All the novel molecules (7a-h) are characterized and most of these compounds showed potent inhibitory activities and are suitable for development of therapeutic medication for breast cancer. The docking studies show good binding with 1XP6.All Paracetamol derivatives of our present invention show greatest activity in the DPPH-assay.The method of preparation of our compound are given as: The first step involves propargylation of Paracetamol by using propargyl bromide and potassium carbonate in DMF (DiMethylFormamide ) medium. The next step involves formation of various substituted Alkyl azides from Aldehydes. (It involves three steps:Aldehyde->Alcohol->Alkyl halide->Alkyl Azide). The final step involves conversion to Paracetamol embedded [1,2,3]-triazoles (7a-h) by reacting Propargylated Paracetamol derivative with various Azides. The figure associated with abstract is Fig. 1.
Patent Information
Application ID | 202441087377 |
Invention Field | CHEMICAL |
Date of Application | 13/11/2024 |
Publication Number | 47/2024 |
Inventors
Name | Address | Country | Nationality |
---|---|---|---|
JOOLAKANTI HIMA BINDHU | Be yes Krishna residency, Flat no.101, Street no.3, Beside lane of Dilip supermarket, lalamma gardens, Manikonda, Telangana - 500089, India. | India | India |
KAMEPALLI RAMANJANEYULU | H.NO.4-76, Bommanampadu, Prakasam, Bommanampadu, Andhra Pradesh – 52320, India. | India | India |
Applicants
Name | Address | Country | Nationality |
---|---|---|---|
JOOLAKANTI HIMA BINDHU | Be yes Krishna residency, Flat no.101, Street no.3, Beside lane of Dilip supermarket, lalamma gardens, Manikonda, Telangana - 500089, India. | India | India |
KAMEPALLI RAMANJANEYULU | H.NO.4-76, Bommanampadu, Prakasam, Bommanampadu, Andhra Pradesh – 52320, India. | India | India |
VISHNU INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH | Vishnu Institute of Pharmaceutical Education and Research Vishnupur, Narsapur, Medak District, Telangana-502313, India | India | India |
Specification
Description:4. DESCRIPTION
Technical Field of the Invention
The present invention relates to the field of pharmaceutical compositions, more specifically to Molecular Hybridization, where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single molecule, as in our present invention, compositions of paracetamol embedded [1,2,3]-triazoles.
Background of the Invention
Paracetamol is most widely used analgesics and antipyretic. Because of its wide use, researchers have begun exploring paracetamol for other uses. Paracetamol is a safe and effective drug when used in normal dose, if excess dosage is taken, it can cause toxicity and irreversible damage to the liver. Along with pain relief and fever reduction, it also haspositive effects on glucose levels in blood, proper functioning of skeletal muscle and used as a neuroprotective and cardioprotective agent. Preclinical studies have shown that these other benefits may be related to paracetamol's ability to act as an antioxidant, and these findings could lead to novel research methods and clinical relevance in other diseases.
When used in the proper prescriptive methods, paracetamol has a protective effect on the heart. It has also been reported to have neuroprotective effects. Maharaj et al. (2004) reported that ex vivo treatment with acetaminophen (0.25-1 mM) could prevent cyanide-induced superoxide anion formation and lipid peroxidation in rat brain homogenates. In addition, Bisaglia et al. (2002) used rat primary hippocampal neurons and rat pheochromocytoma cells showed that acetaminophen (100 μM) can protect against amyloid beta-fragment-induced impairment of mitochondrial redox activity, increases in phospholipid peroxidation, and apoptotic nuclear fragmentation, suggesting a possible therapeutic effect of paracetamol on Alzheimer's disease.
Extensive animal and in vitro studies have shown that paracetamol has remarkable antioxidant properties when used in therapeutic dosage. Acetaminophen has a phenolic structure with a substituent at the para position relative to the hydroxyl group which allowing it to react with reactive species (Dinis et al., 1994). Shertzer et al. (2008) observed that paracetamol at concentrations of 2-10 μM is able to directly scavenge reactive oxygen. Nam et al. (2009) reported that paracetamol has higher reactivity with peroxyl radicals than many widely used phenolic antioxidants, including ubiquitous butylated hydroxytoluene (BHT).
The 1,2,3-Triazoles are considered more than just passive linkers and offers properties such as moderate dipole character, ability to form hydrogen bonds, rigidity and stability in vivo. SAR studies have shown that the group attached to the nitrogen atom at the first position has the greatest difference in structure and properties.
Rosivaldo S. Borgeset al., reported that Paracetamol has more antioxidant properties than salicylic acid in many several oxidative stress-forced models. Vivek Gupta et al., reported a series of Paracetamol incorporated Shiff Bases. These derivatives are prepared from condensation of 4- acetamidophenoxyacetyl-Hydrazide with various aldehydes. The newly synthesized compounds are evaluated for antibacterial and antifungal activities. The synthesized compounds showed good antimicrobial activity.
A few patents related to our present invention have been discussed below:
The patent "Azolo-pyrimidine for the treatment of cancer-related disorders" (TWI812494B) relates to the compositions and method of preparation of compounds that is an inhibitor of at least one of the A 2Aand A 2Badenosine receptors.
The patent "Compositions, Formulations, and Methods for Treating Eye Diseases" (JP6865254B2) relates to pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt or zwitterion, and cyclodextrin.
The patent "Synthesis Of Paracetamol Linked Triazole Derivatives And Their Therapeutic Use" (IN365543) refers to the process for preparing paracetamol linked 1,2,3-triazole derivatives compound of formula (I),wherein, R is independently benzyl or substituted benzyl and benzoyl or substituted benzoyl groups or its pharmaceutically acceptable salts.
Our present invention relates to the compositions of paracetamol embedded [1,2,3]-triazoles wherein the two pharmacophores i.e. Paracetamol and Triazoles are combined by click chemistry approach.
Brief Summary of the Invention
The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure and it does not identify key/critical elements of the invention or delineate the scope of the invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later.
The primary objective of this invention is to to combine the two pharmacophores i.e. Paracetamol and Triazoles as Paracetamol embedded [1,2,3]-triazole derivatives by click chemistry approach.
Another objective of our present invention is to present new compositions which have better scavenging activity levels along with potent inhibitory activities.
Another objective of our present invention is to present new compositions that can be utilized for the treatment for breast cancer.
The present invention relates to compositions of substituted Paracetamol embedded [1,2,3]-triazole derivatives whose synthesis involves cycloaddition of Propargylated Paracetamol derivative with variously substituted Azides to yield Paracetamol embedded [1,2,3]-triazolederivatives (7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h which are hereby referred to as 7a-h) by applying Click-Chemistry approach. The first step involves propargylation of Paracetamol by using propargyl bromide and potassium carbonate in DMF (Dimethyl Formamide) medium. The next step involves formation of various substituted Alkyl azides from Aldehydes. (It involves three steps: Aldehyde-> Alcohol->Alkyl halide->Alkyl Azide). The final step involves conversion to Paracetamol embedded [1,2,3]-triazoles (7a-h) by reacting Propargylated Paracetamol derivative with various Azides.
Synthesis of Paracetamol embedded [1,2,3-Triazole] derivatives is performed by applying click concept, in accordance with our present invention. The catalytic reaction is easy to perform, it can be carried out in aqueous conditions even at room temperature, and allows the forms 1,4-disubstituted regioisomers preferentially.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, the detailed description and specific examples, while indicating preferred embodiments of the invention, will be given by way of illustration along with complete specification.
Brief Summary of the Drawings
The invention will be further understood from the following detailed description of a preferred embodiment taken in conjunction with an appended drawing, in which:
Fig. 1 (100) illustrates the diagram of Synthesis of N-(4-((1R-1,2,3-triazol-4-yl) methoxy) phenyl) acetamides(7a-7h), in accordance with the exemplary embodiment of the present invention.
Fig. 2 (200) showing interactions of Paracetamol derivatives at active site of 1XP6, in accordance with the exemplary embodiment of the present invention.
Detailed Description of the Invention
The present disclosure emphasises that its application is not restricted to specific details of construction and component arrangement, as illustrated in the drawings. It is adaptable to various embodiments and implementations. The phraseology and terminology used should be regarded for descriptive purposes, not as limitations.
The terms "including," "comprising," or "having" and variations thereof are meant to encompass listed items and their equivalents, as well as additional items. The terms "a" and "an" do not denote quantity limitations but signify the presence of at least one of the referenced items. Terms like "first," "second," and "third" are used to distinguish elements without implying order, quantity, or importance.
The present invention relates to compositions of Paracetamol embedded [1,2,3]-triazoles. The method of preparation of the paracetamol embedded [1,2,3]-triazoles involves five steps:
STEP-1: Synthesis of Propargylated Paracetamol (6a):
"Under nitrogen atmosphere, 5 mmol of Paracetamol is added to 8mL of Di methyl Formamide and then after add 10 mmol of Potassium carbonate and 5 mmol of Propargyl bromide. The resulting reaction mixture is stirred for 12 h at room temparature and completion of reaction is monitored by thin layer chromatography. After completion of reaction, add ice, citric acid and stir the mixture again for 1 h. The product is filtered, dried and subjected to column chromatography for purification."
STEP-2: Synthesis of Aryl Alcohols (2a-h):
"Under nitrogen atmosphere 5.9 mmol of Aryl Aldehyde (1a-h) is added to 10 mL of Methanol and then add 24 mmol of Sodium borohydride. The resulting reaction mixture is stirred at 0°c for 2 h and reaction is monitored by thin layer chromatography.Methanol is evaporated then the residue is added to EtOAc and water mixture. The Ethyl acetate layer is collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification."
STEP-3: Synthesis of Alkyl Bromides (3a-h):
"Under nitrogen atmosphere, 1 g of Aryl Alcohol (2a-h) is added to 10 mL of Ether and then add 0.5 equiv of Phosphorus tribromide. The resulting reaction mixture is stirred at 0 °c for 0.5 h and then after the residue is added to EtOAc and water mixture. The Ethyl acetate layer is collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification."
STEP-4: Synthesis of Alkyl Azides (4a-h):
"Under nitrogen atmosphere, 2 equiv of Sodium azide and Tetrabutylammonium bromide is added to a solution of Alkyl halide (3a-h) (1 g) in 4:8 aqueous Dichloromethane. The resulting reaction mixture is stirred for 12 hours at room temparature and then after the residue is added to Dichloromethane and water mixture. The Dichloromethane layer is collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification."
Synthesis of Paracetamol embedded [1,2,3]-triazole derivatives by using CLICK CHEMISTRY Approach (7a-h):
"Under nitrogen atmosphere, 1 g of (N-(3-(prop-2-ynyloxy)phenyl) acetamide (6a) is added to
7:8 aqueous THF then add 1.1 equiv of azide (4a-h), 200 mg of sodium ascorbate and 0.25 mmol of copper sulphate pentahydrate. The resulting reaction mixture is stirred for 8 h at room temparature and then after the residue is added to Ethyl acetate and water mixture. The Ethyl acetate layer is collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification."
Docking
The "Human Estrogen Receptor Alpha Ligand-Binding Domain (PDB Code: 1XP6)"was selected as the Target are our proposed compounds bind at a resolution of 2.8 Ǻ, 1.5 Ǻ and 1.95 Ǻ respectively.
The 1XP6 is used as the receptor for this study due to the structural similarity of its ligand with our synthesized compounds (7a-7h).The Docking studies suggested that designed compounds (7a-7h) have good binding ability with 1XP6. Docking scores of compounds are in the range of -7.522 to -10.285 representing their potential for binding at 1XP6 (Table 1). The highest docking scores (>-9.00) are reported for compounds 7a, 7b, 7d, 7f and 7g.
Most of the molecules have shown strong H-bond interactionsand therefore this could be the reason for the good binding affinities observed with this class of compounds. The NH group of Compounds 7a, 7b, 7d, 7f and 7g has shown strong H-bond interaction withLYS 531. The Carbonyl group of Compound 7eformed Hydrogen bond with LEU 536 and NH group formed Hydrogen bond with TYR 526.The Nitro group of Compound 7hformed Hydrogen bond with GLU 353 and ARG 394.This could be the reason for their high cytotoxic activity (Figure).
Fig 2shows the interactions of Paracetamol derivatives at active site of 1XP6, in accordance with our present invention, wherein, (A) shows The NH group of Compound 7a formed Hydrogen bond with LYS 531 and Benzene ring formed strong hydrophobic interaction with PHE404. (B) Shows the NH group of Compound 7b formed Hydrogen bond with LYS 531 and Benzene ring formed strong hydrophobic interaction with PHE 404. (C) shows that the compound 7c did not form any interactions.(D) shows the NH group of Compound 7dformed Hydrogen bond with LYS 531, Di Chloro Benzyl ring formed strong hydrophobic interaction with PHE 404.(E) shows Carbonyl group of Compound 7eformed Hydrogen bond with LEU 536 and NH group formed Hydrogen bond with TYR 526.(F) shows the NH group of Compound 7f formed Hydrogen bond with LYS 531.(G) shows the NH group of Compound 7gformed Hydrogen bond with LYS 531. (H) Shows the Nitro group of Compound 7hformed Hydrogen bond with GLU353 and ARG 394.
Table 1 Docking Results of Paracetamol embedded [1,2,3]- triazoles (7a-h):
Comp. Dock Score No Of
H-Bonds Interacting Amino
Acids H-Bond Distance (Å) Glide Energy Emodel Energy
7a -9.67 1 LYS 531 2.15 -48.754 -78.174
7b -9.433 1 LYS 531 1.89 -45.583 -72.221
7c -8.051 0 - - -47.054 -63.981
7d -9.04 1 LYS 531 2.20 -48.721 -77.025
7e -8.402 2 LEU 536, TYR 526 2.17 -50.593 -75.72
7f -10.145 1 LYS 531 1.92 -45.59 -70.782
7g -10.285 1 LYS 531 1.93 -44.667 -69.745
7h -7.522 0 GLU 353, ARG 394 - -50.933 -71.642
Biological Activity
3.4.3.1. Cytotoxicity test by MTT assay
The synthesized Paracetamol embedded [1,2,3]-triazoles are evaluated for Cytotoxicity. This activity is performed on MCF7 cell line by using MTT Assay.
The in vitro cytotoxicity of the designed novel molecules (7a-h) is evaluated against human cancer cell line MCF-7 (breast). The molecules are screened for MTT assay against breast cancer cell line at different concentrations ranging from 125 µg/mL to 12.5 µg/mL to determine the percentage growth inhibition. The results are depicted in Table 2. Compounds 7b with 3- Methyl Benzyl, 7h with 4-Nitro Benzyl and 7a with 2-Methyl Benzyl groups on the Triazole ring at N-1 are most active with an IC50 value of 20.84, 21.45, 23.10 µg/mlrespectively and two fold less active than the standard drugTamoxifen IC50 value.Compounds 7f with 2-Fluoro Benzyl, 7g with 3-Fluoro Benzyl and 7d with 2,4-Di Chloro Benzyl groups on Triazole ring have good cytotoxic activity with an IC50 value of 35.56, 38.18, 40.57µg/mlrespectively while compounds 7e with 3,4-Di Chloro Benzyl, 7c with 4- Methyl Benzyl groups are least active ones with an IC50 value of >40 µg/ml.
Compounds with Methyl substitution on Benzyl group at 2, 3 position increase the cytotoxic activity but with Methyl substitution at 4 position decreases the activity. Compounds with Nitro substitution on Benzyl group at 4 position increase the cytotoxic activity. Compounds with Di chloro substitution on Benzyl group at 2, 4 and 3, 4 position decreases the cytotoxic activity. Compounds with Fluoro substitution on Benzyl group at 2, 3 position increase the cytotoxic activity.
Table 2 Cytotoxic activity of test compounds (7a-h) against MCF-7 cell line obtained by MTT assay: (Expressed as CTC50 in µg/mL)
Comp. R MCF-7
7a 2-Methyl Benzyl 23.10±0.13
7b 3- Methyl Benzyl 20.84±0.17
7c 4- Methyl Benzyl 56.83±0.5
7d 2,4-Di Chloro Benzyl 40.57±0.8
7e 3,4-Di Chloro Benzyl 47.10±0.35
7f 2-Fluoro Benzyl 35.56±0.16
7g 3-Fluoro Benzyl 38.18±0.9
7h 4-Nitro Benzyl 21.45±0.8
Tamoxifen 9.15
Antibacterial activity
Individually Paracetamol and Triazoles are reported to possess Antibacterial activity, the synthesized Paracetamol embedded [1,2,3]-triazoles are evaluated for Antibacterial activity. By using Disk diffusion technique minimum inhibitory concentration (MIC) values are determined for each compound.
Antioxidant activity
The synthesized Paracetamol embedded [1,2,3]-triazoles are evaluated for Antioxidant activity and the results shown in table 3.
Reactive oxygen species are involved in several cell death related neuronal diseases. So, synthesized compounds are also tested for their abilities to scavenge DPPH. Almost all the compounds exhibited outstanding activity except 7h. Compounds 7a with 2-Methyl Benzyl, 7b with 3- Methyl Benzyl, 7c with 4- Methyl Benzyl, 7d with 2,4-Di Chloro Benzyl, 7e with 3,4-Di Chloro Benzyl, 7f with 2-Fluoro Benzyl, 7g with 3-Fluoro Benzyl groups are found to be the most potent Antioxidants and having a IC50 value of < 30 µM i.e more active than Standard. Compound 7h with 4-Nitro Benzyl is found to be the less potent Antioxidant and having a IC50 value of 272.21 µM.
Compounds with Fluoro substitution on Benzyl group at 2, 3 position, Di Chloro substitution on Benzyl group at 2, 3 or 3,4 position, Methyl substitution on Benzyl group at 2, 3, 4 position increase the Antioxidant activity. Compound with Nitro substitution on Benzyl group at 4 position decrease the Antioxidant activity.
Table 3 Antioxidant activity of test compounds (7a-h) obtained by DPPH method: (Expressed as IC50 in µM)
Comp. R DPPH Scavenging
7a 2-Methyl Benzyl 26.75
7b 3- Methyl Benzyl 23.78
7c 4- Methyl Benzyl 29.72
7d 2,4-Di Chloro Benzyl 20.44
7e 3,4-Di Chloro Benzyl 23.00
7f 2-Fluoro Benzyl 29.38
7g 3-Fluoro Benzyl 23.50
7h 4-Nitro Benzyl 272.21
Ascorbic acid 30.81±1.01
Antibacterial activity
The synthesized triazoles(7a-h) are tested for in-vitro Antibacterial activity using four bacterial strains, one Gram-positive (Staphylococcus aureus) and three Gram-negative (Escherichia coli, Proteus vulgaris and Pseudomonas aeruginosa) by Disk diffusion technique using Gentamicin as standard drug and the results shown in table 4.
Among the Paracetamol embedded 1,2,3- Triazoles, Methyl, Fluoro groups substituted at benzyl of the Triazole compounds i.e 7a, 7b, 7c, 7f and 7gwere active against Staphylococcus aureus with a MIC value of <3000 µM.Di Chloro and Nitro substituted compounds i.e 7d, 7e and 7hwere inactive against Staphylococcus aureus, E.coli and Pseudomonas aeruginosa.Compound 7f with 2-F Benzyl group is most active against E.coli with a MIC value of <150 µM and two fold less active than the standard drug Gentamicin. Compound 7g with 3-F Benzyl group is active against E.coli with a MIC value of <300 µM and four fold less active than Gentamicin. Methyl substituted compounds i.e 7a, 7b and 7cwere less active against E.coli with a MIC value of <3000 µM. Compound 7f with 2-F Benzyl group is most active against Pseudomonas aeruginosa with a MIC value of <150 µM. Compound 7g with 3-F Benzyl group is active against Pseudomonas aeruginosa with a MIC value of <300 µM. Methyl substituted compounds i.e 7a, 7b and 7cwere less active against Pseudomonas aeruginosa with a MIC value of <3000 µM. 7fwith 2-F Benzyl group, 7gwith 3-F Benzyl group and 7hwith 4-NO2 Benzyl group are most active against Proteus vulgariswith a MIC value of <150 µM. 7dwith 2,4-Di Cl Benzyl group and 7ewith 3,4-Di Cl Benzyl group are active against Proteus vulgariswith a MIC value of 255 µM.Methylated compounds i.e. 7a, 7b and 7cwere less active against Proteus vulgaris with a MIC value of 2972.73 µM, 1486.36 µM respectively.
Compounds which contain Methyl at 2,3,4 positions of Benzyl group and Fluoro at 2,3 positions of Benzyl group are active towards Gram positive bacteriaStaphylococcus aureus butDi Chloro substitution at 2,4 or 3,4 positions and Nitro substitution at 4 position of Benzyl group destroys the activity and the compounds are inactive. Compounds which contain Fluoro at 2,3 positions of benzyl group are most active towards the Gram negative bacteria but Addition of Methyl group at 2,3,4 positions of benzyl group decreases the activity and the compounds are less active. Addition of Chlorine at 2,4 or 3,4 positions and Nitro group at 4th position of Benzyl group destroys the activity towards E.coli and Pseudomonas aeruginosa but most active towards Proteus vulgaris.
Table 4 Antibacterial activity of Substituted Paracetamol embedded [1,2,3]-triazoles: (MIC in µM)
Comp. R S.aureus E.coli P.aeruginosa P.vulgaris
7a 2-Methyl Benzyl 2972.73 2972.73 2972.73 2972.73
7b 3- Methyl Benzyl 2972.73 2972.73 2972.73 1486.36
7c 4- Methyl Benzyl 2972.73 2972.73 2972.73 1486.36
7d 2,4-Di Chloro Benzyl - - - 255.59
7e 3,4-Di Chloro Benzyl - - - 255.59
7f 2-Fluoro Benzyl 2938.15 146.90 146.90 146.90
7g 3-Fluoro Benzyl 2938.15 293.81 293.81 146.90
7h 4-Nitro Benzyl - - - 136.10
Gentamicin <2.09 >67.00 <4.18 <4.18
Spectral studies:
The Scaffold is designed based on the Literature followed bydocking studies. Eight variously substituted Paracetamol embedded [1,2,3]-triazoles are prepared (7a-h).
The first step involves propargylation of Paracetamol by using propargyl bromide and pottasium carbonate in DMF medium.
The 1H-NMR spectrum (400 MHz, DMSO,Fig.3.6)of compound PAR-PRO (6a) showed the characteristic signals at δ (ppm)2.00 (3H, s), 3.53 (1H, s), 4.74 (2H, d), 6.91 (2H, d), 7.48 (2H, d), 9.80 (1H, s).
The signal at 2.00 (3H, s) indicates the presence of Methyl protons.
The signal at 3.53 (1H, s)and indicates the presence of Propynyl proton.
The signal at 4.74 (2H, d) indicates the presence of Methoxy protons.
The signal at 6.91 (2H, d), 7.48 (2H, d) and 9.80 (1H, s) indicates the presence of Aromatic Phenyl protons and Amide proton.
The 13C-NMR spectrum (400 MHz, DMSO, Fig.2) of compound PAR-PRO (6a) exhibited the characteristic signals at δ (ppm)23.7, 55.5, 78.0, 79.3, 114.9, 120.4, 133.1, 152.8, 167.7.
The signal at 23.7 indicates the presence of Methyl Carbon.
The signal at 55.5 indicates the presence of Methoxy Carbon.
The signals at 78.0 and 79.3 indicate the presence of Propynyl Carbons.
The signals at 114.9, 120.4, 133.1 and 152.8 indicate the presence of Phenyl ring Carbons.
The signal at 167.7 indicates the presence of Carbonyl carbon of Amide.
The next step involves formation of various substituted Alkyl azides from Aldehydes.The final step involves conversion to Paracetamol embedded [1,2,3]-triazoles (7a-h) by using click concept.
Table 5List of novel Paracetamol embedded [1,2,3]-triazoles synthesized
S.no. Comp. Structure Yield
1. 7a
69
2. 7b
95
3. 7c
86
4. 7d
60
5. 7e
98
6. 7f
80
7. 7g
97
8. 7h
60
All the above novel compounds showed distinctive absorption "bandsin the IR spectra (cm-1) i.e.3060-3330 (N-H, Amide),1650-1700 (C=O Amide)",1000-1300 (C-O, Phenol),1500-1600 (C=C Aromatic),3000-3100 (C-H Aromatic),<900(C-H (B), Aromatic),800-1200 (C-C Aliphatic), 1300-1450 (C-H, (B) Aliphatic).
"The 1H-NMR spectra showed the distinctive peaks in between δ 2.00 ppm and 9.78 ppm."This also showed the peaks of aliphatic methyl protons of Paracetamol and Benzyl ring atδ 2.00-2.35 ppm,methylene protons at δ 5.08-5.80 ppm, Triazole proton at δ 7.15-7.66 ppm,Aromatic protons at δ 6.89-9.78 ppm, and Amide proton at δ 7.38-9.77 ppm."The 13C-NMR spectra exhibited the characteristic peaks of thecarbonyl carbons in between δ 163-168 ppm,Methyl Carbons in between δ 18-24 ppm, Methylene Carbons in between δ 46-62 ppm,Triazole carbons in betweenδ 120-144ppm,Aromatic carbons in betweenδ 114-161ppm."The Mass spectra of the novel compounds showed M+, [M+1], [M+2]ions.
e.g.7d
The Mass spectrum shows M+-391 & M+2-393 peaks. "The I.R (cm-1) spectrum, showed the characteristic absorption bands at 823(Para Substituted Benzene), 962 (C-H (B), Aromatic), 1180 (C-C, Aliphatic), 1242 (C-O, Phenol), 1319 (C-H, (B) Aliphatic), 1506 (C=C, Aromatic), 1656 (C=O, Amide), 3088 (C-H, Aromatic) and 3292 (N-H, Amide)."
"The 1H-NMR spectrum (400 MHz, DMSO) of 7dexhibited the peaks at δ (ppm)2.00 (3H, s), 5.09 (2H, s), 5.70 (2H, s), 6.95 (2H, d), 7.24 (1H, d), 7.47 (3H, m), 7.71 (1H, d), 8.24 (1H, s), 9.77 (1H, s)."
"The signal at 2.00 (3H, s)-Methyl protons."
"The signal at 5.09 (2H, s)-Benzyl protons."
"The signal at 5.70 (2H, s)-Methoxy protons."
"The signals at 6.95 (2H, d), 7.24 (1H, d), 7.47 (3H, m), 7.71 (1H, d), 8.24 (1H, s) indicates the presence of Aromatic protons and Triazole proton."
"The signal at 9.77 (1H, s) indicates the presence of Amide proton."
The 13C-NMR spectrum (400 MHz, DMSO) of compound 7dexhibited the characteristic signals at δ (ppm)23.7, 50.0, 61.1, 114.7, 120.3, 125.0, 127.8, 129.1, 131.8, 132.3, 132.8, 133.6, 133.9, 143.0, 153.6, 167.7.
The signal at 23.7 indicates the presence of Methyl Carbon.
The signal at 50.0 indicates the presence of Benzyl Carbon.
The signal at 61.1 indicates the presence of Methoxy Carbon.
The signals at 120.3 and 143.0 indicate the presence of Triazole ring Carbons.
The signals at 114.7, 125.0, 127.8, 129.1, 131.8, 132.3, 132.8, 133.6, 133.9 and 153.6 indicate the presence of Aromatic Carbons.
The signal at 167.7 indicates the presence of Carbonyl carbon of Amide.
Compounds 7a,7b,7c,7d,7e,7f and 7gshow potent Antioxidant activity with IC50 valueof< 30 µM i.e. DPPH scavenging activity levels more than that of Positive control.Compounds 7a, 7b, 7c, 7f and7g are most active against Staphylococcus aureus with a MIC value of <3000 µM,Compounds 7f and7g are most active against E.coli and Pseudomonas aeruginosa with a MIC value of <300 µM while compounds 7d, 7e, 7f, 7g and7h are most active against Proteus vulgaris with a MIC value of <255µM.
Physical data of synthesized compounds
Table 6. Physical Characterization data of Paracetamol embedded [1,2,3]-triazoles
Comp. R Molecular
Formula Relative
Molecular
Mass
(RMM) m.p.
(oC) Yield
%
7a
C19H20N4O2
336.39 175-177 69
7b
C19H20N4O2
336.39 184-186 95
7c
C19H20N4O2
336.39 190-192 86
7d
C18H16Cl2 N4O2
391.25 141-143 60
7e
C18H16Cl2 N4O2
391.25 133-135 98
7f
C18H17FN4O2
340.35 160-162 80
7g
C18H17FN4O2
340.35 172-174 97
7h
C18H17N5O4
367.36 187-189 60
Spectral data of synthesized compounds
"(N-(4-(prop-2-ynyloxy)phenyl)acetamide"
White solid, 80% yield.
mp: 150-152°C.
"1H-NMR (400 MHz, DMSO) δ:2.00 (3H, s, NH-CO-CH3), 3.53 (1H, s, Propynyl), 4.74 (2H, d, J=2.1 Hz, O-CH2), 6.91 (2H, d, J=9.2 Hz, H-3,5 (Phenyl)), 7.48 (2H, d, J=9.2 Hz, H-2,6 (Phenyl)), 9.80 (1H, s, NH-CO-CH3)."
"13C-NMR (400 MHz, DMSO) δ: 23.7 (CH3, NH-CO-CH3), 55.5 (CH2, O-CH2), 78.0 (CH, C-1',Propynyl), 79.3 (C, C-2',Propynyl), 114.9 (CH, C-3, C-5, Phenyl), 120.4 (CH, C-2, C-6, Phenyl), 133.1 (C, C-1, Phenyl), 152.8 (C, C-4, Phenyl), 167.7 (C=O, NH-CO-CH3)."
"N-(4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7a)
White solid,69% yield.
mp: 175-177°C.
"1H-NMR (400 MHz, CDCl3) δ: 2.14 (3H, s, NH-CO-CH3), 2.28 (3H, s, C6H4-CH3)", 5.13 (2H, s, C6H5-CH2), 5.54 (2H, s, O-CH2), 6.89 (2H, d, J=9.2 Hz, H-3,5 (Phenyl)), 7.16 (1H, d, J=7.0 Hz, H-3" (Benzyl)), 7.15-7.31 (4H, m, H-4", 5", 6" (Benzyl), H-5' (Triazole)), 7.38 (3H, t, J=9.2 Hz, H-2,6 (Phenyl), NH-CO-CH3).
13C-NMR (400 MHz, CDCl3) δ: 18.9 (CH3, Benzyl), 24.1 (CH3, NH-CO-CH3), 52.3 (CH2, C6H5-CH2), 62.1 (CH2, O-CH2), 114.9 (CH, C-3, C-5, Phenyl), 121.8 (CH, C-5', Triazole), 122.5 (CH, C-2, C-6, Phenyl), 126.6 (CH, C-4'', Benzyl), 129.1 (CH, C-5'', Benzyl), 129.3 (CH, C-3'', Benzyl), 131.0 (CH, C-6'', Benzyl), 131.7 (C, C-1, Phenyl), 132.2 (C, C-2'', Benzyl), 136.8 (C, C-1'', Benzyl), 144.1 (C, C-4', Triazole), 154.7 (C, C-4, Phenyl), 168.5 (C=O, NH-CO-CH3). IR (ATR) cm-1, ν: 821 (C-H (B), Aromatic), 1006 (C-C, Aliphatic), 1220 (C-O, Phenol), 1317 (C-H, (B) Aliphatic), 1506 (C=C, Aromatic), 1660 (C=O, Amide), 2312 (C-H, Aliphatic), 3082 (N-H, Amide).
MS (ESI) m/z: 337 [M + 1],C19H20N4O2.
"N-(4-((1-(3-methyl benzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7b)
White solid,95% yield.
mp: 184-186°C.
"1H -NMR (400 MHz, CDCl3) δ: 2.15 (3H, s, NH-CO-CH3), 2.34 (3H, s, C6H4-CH3)", 5.15 (2H, s, C6H5-CH2), 5.48 (2H, s, O-CH2), 6.90 (2H, d, J=9.2 Hz, H-3,5 (Phenyl)), 7.07 (2H, d, J=7.8 Hz, H-2", 4" (Benzyl)), 7.18(2H, t, J=9.2 Hz, H-5", 6" (Benzyl)), 7.25-7.28 (1H, m, H-5' (Triazole)), 7.38 (2H, d, J=9.2 Hz, H-2,6 (Phenyl)), 7.51 (1H, s, NH-CO-CH3).
13C-NMR (400 MHz, CDCl3) δ: 21.2 (CH3, NH-CO-CH3), 24.1 (CH3, Benzyl), 54.1 (CH2, C6H5-CH2), 62.0 (CH2, O-CH2), 114.9 (CH, C-3, C-5, Phenyl), 121.9 (CH, C-5', Triazole), 122.7 (CH, C-2, C-6, Phenyl), 125.1 (CH, C-4'', Benzyl), 128.7 (CH, C-6'',Benzyl), 128.9 (CH, C-5'', Benzyl), 129.5 (C, C-1, Phenyl), 131.7 (CH, C-2'', Benzyl), 134.2 (C, C-1'', Benzyl), 138.9 (C, C-3'', Benzyl), 144.3 (C, C-4', Triazole), 154.7 (C, C-4, Phenyl), 168.6 (C=O, NH-CO-CH3).IR (ATR) cm-1, ν: 1192 (C-C Aliphatic), 1232 (C-O, Phenol), 1367 (C-F), 1539 (C=C Aromatic), 1743 (C=O Amide), 2370 (C-H, Aliphatic), 2918 (N-H, Amide).
MS (ESI) m/z: 337 [M + 1], C19H20N4O2.
"N-(4-((1-(4-methyl benzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7c)
White solid,86% yield.
mp: 190-192°C.
"1H -NMR (400 MHz, CDCl3) δ: 2.15 (3H, s, NH-CO-CH3), 2.35 (3H, s, C6H4-CH3)", 5.14 (2H, s, C6H5-CH2), 5.48 (2H, s, O-CH2), 6.90 (2H, d, J=8.7 Hz, H-3,5 (Phenyl)), 7.18 (5H, s, H-2", 3", 5", 6" (Benzyl), H-5' (Triazole)), 7.37 (2H, d, J=9.2 Hz, H-2,6 (Phenyl)), 7.49 (1H, s, NH-CO-CH3).
13C-NMR (400 MHz, CDCl3) δ: 21.1 (CH3, NH-CO-CH3), 24.1 (CH3, Benzyl), 54.0 (CH2, C6H5-CH2), 62.1 (CH2, O-CH2), 114.9 (CH, C-3, C-5, Phenyl), 121.9 (CH, C-5', Triazole), 122.5 (CH, C-2, C-6, Phenyl), 128.1 (CH, C-2'', C-6'', Benzyl), 129.7 (CH, C-3'', C-5'', Benzyl), 131.3 (C, C-1, Phenyl), 131.6 (C, C-1'', Benzyl), 138.7 (C, C-4'', Benzyl), 144.3 (C, C-4', Triazole), 154.8 (C, C-4, Phenyl), 168.4 (C=O, NH-CO-CH3).IR (ATR) cm-1, ν: 806 (Para Substituted Benzene), 991 (C-H (B), Aromatic), 1222(C-C, Aliphatic), 1296 (C-O, Phenol), 1504 (C=C, Aromatic), 1676 (C=O, Amide), 3005(C-H, Aromatic), 3282 (N-H, Amide).
MS (ESI) m/z: 337 [M + 1], C19H20N4O2.
"N-(4-((1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7d)
Brown solid, 60% yield.
mp: 141-143°C.
"1H -NMR (400 MHz, DMSO) δ: 2.00 (3H, s, NH-CO-CH3), 5.09 (2H, s, C6H5-CH2)", 5.70 (2H, s, O-CH2), 6.95 (2H, d, J=8.7 Hz, H-3,5 (Phenyl)), 7.24 (1H, d, J=8.3 Hz, H-6" (Benzyl)), 7.47 (3H, m, H-3", 5"(Benzyl), H-5' (Triazole)), 7.71 (1H, d, J=2.1 Hz, H-2 (Phenyl)), 8.24 (1H, s, H-6 (Phenyl)), 9.77 (1H, s, NH-CO-CH3).
13C-NMR (400 MHz, DMSO) δ: 23.7 (CH3, NH-CO-CH3), 50.0 (CH2, C6H5-CH2), 61.(CH2, O-CH2), 114.7 (CH, C-3, C-5, Phenyl), 120.3 (CH, C-5', Triazole), 125.0 (CH, C-2, C-6, Phenyl), 127.8 (CH, C-5'', Benzyl), 129.1 (CH, C-3'', Benzyl), 131.8 (C, C-1, Phenyl), 132.3 (CH, C-6'', Benzyl), 132.8 (C, C-4'', Benzyl), 133.6(C, C-2'', Benzyl), 133.9(C, C-1'', Benzyl), 143.0(C, C-4', Triazole), 153.6(C, C-4, Phenyl), 167.7(C=O, NH-CO-CH3). IR (ATR) cm-1, ν: 823 (Para Substituted Benzene), 962 (C-H (B), Aromatic), 1180 (C-C, Aliphatic), 1242 (C-O, Phenol), 1319 (C-H, (B) Aliphatic), 1506 (C=C, Aromatic), 1656 (C=O, Amide), 3088 (C-H, Aromatic), 3292 (N-H, Amide).
MS (ESI) m/z: 391 [M+], 393 [M + 2], C18H16Cl2 N4O2.
"N-(4-((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7e)
"White solid,98% yield."
"mp: 133-135°C."
"1H -NMR (400 MHz, DMSO) δ: 2.00 (3H, s, NH-CO-CH3), 5.09 (2H, s, C6H5-CH2)", 5.63 (2H, s, O-CH2), 6.95 (2H, d, J=9.2 Hz, H-3,5 (Phenyl)), 7.28 (1H, d, J=1.7 Hz, H-6" (Benzyl)), 7.47 (2H, d, J=9.2 Hz, H-2", 5"(Benzyl)), 7.62-7.66 (2H, m, H-5' (Triazole), H-2 (Phenyl)), 8.31 (1H, s, H-6 (Phenyl)), 9.77 (1H, s, NH-CO-CH3).
13C-NMR (400 MHz, DMSO) δ: 23.7 (CH3, NH-CO-CH3), 51.4 (CH2, C6H5-CH2), 61.2 (CH2, O-CH2), 114.7 (CH, C-3, C-5, Phenyl), 120.4 (CH, C-5', Triazole), 124.7(CH, C-2, C-6, Phenyl), 128.3 (CH, C-6'', Benzyl), 130.0 (CH, C-5'', Benzyl), 130.9 (CH, C-2'', Benzyl), 130.9(C, C-4'', Benzyl), 131.2 (C, C-1, Phenyl), 132.8 (C, C-3'', Benzyl), 136.9 (C, C-1'', Benzyl), 143.2 (C, C-4', Triazole), 153.6 (C, C-4, Phenyl), 167.7 (C=O, NH-CO-CH3). IR (ATR) cm-1, ν: 748 (Ordho Substituted Benzene), 821 (Para Substituted Benzene), 1130 (C-C, Aliphatic), 1219(C-O, Phenol), 1319 (C-H, (B) Aliphatic), 1610 (C=C, Aromatic), 1660 (C=O, Amide), 3080 (N-H, Amide).
MS (APCI) m/z: 391 [M+], 392 [M + 21], C18H16Cl2N4O2.
"N-(4-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7f)
"White solid,80% yield."
"mp: 160-162°C."
"1H -NMR (400 MHz, DMSO) δ: 2.00 (3H, s, NH-CO-CH3), 5.08 (2H, s, C6H5-CH2)", 5.67 (2H, s, O-CH2), 6.94 (2H, d, J=9.2 Hz, H-3,5 (Phenyl)), 7.20-7.28 (2H, m, H-3", 5"(Benzyl)), 7.31-7.35 (1H, m, H-6"(Benzyl)), 7.40-7.49 (3H, m, H-4"(Benzyl), H-5' (Triazole), H-2 (Phenyl)), 8.24 (1H, s, H-6 (Phenyl)), 9.77 (1H, s, NH-CO-CH3).
13C-NMR (400 MHz, DMSO) δ:23.7 (CH3, NH-CO-CH3), 46.8 (CH2, C6H5-CH2), 61.1 (CH2, O-CH2), 114.6 (CH, C-3, Phenyl), 115.4 (CH, C-5, Phenyl), 115.6 (CH, C-3'', Benzyl), 120.4 (CH, C-5', Triazole), 122.7 (CH, C-2, Phenyl), 122.8 (CH, C-6, Phenyl), 124.7 (CH, C-5'', Benzyl), 124.7 (C, C-1'', Benzyl), 130.6 (CH, C-4'', Benzyl), 130.7 (CH, C-6'', Benzyl), 132.8 (C, C-1, Phenyl), 143.0 (C, C-4', Triazole), 153.6 (C, C-4, Phenyl), 161.2 (C, C-2'', Benzyl), 167.7 (C=O, NH-CO-CH3).IR (ATR) cm-1, ν: 841 (Para Substituted Benzene), 1093 (C-O, Phenol), 1176 (C-C, Aliphatic), 1409 (C-H, (B) Aliphatic), 1594 (C=C, Aromatic), 1679 (C=O, Amide), 2931 (C-H, Aliphatic), 3053 (C-H, Aromatic), 3259 (N-H, Amide).
MS (APCI) m/z: 339 [M -1], C18H17FN4O2.
"N-(4-((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7g)
White solid,97% yield.
mp: 172-174°C.
"1H -NMR (400 MHz, DMSO) δ: 2.00 (3H, s, NH-CO-CH3), 5.09 (2H, s, C6H5-CH2)", 5.64 (2H, s, O-CH2), 6.95 (2H, d, J=8.7 Hz, H-3,5 (Phenyl)), 7.13-7.20 (3H, m, H-2", 4", 6" (Benzyl)), 7.40-7.49 (3H, m, H-5"(Benzyl), H-5' (Triazole), H-2 (Phenyl)), 8.30 (1H, s, H-6 (Phenyl)), 9.77 (1H, s, NH-CO-CH3).
13C-NMR (400 MHz, DMSO) δ: 23.7 (CH3, NH-CO-CH3), 52.1 (CH2, C6H5-CH2), 61.2 (CH2, O-CH2), 114.7 (CH, C-4'', Benzyl), 114.8 (CH, C-3, Phenyl), 115.0 (CH, C-5, Phenyl), 120.4 (CH, C-2'', Benzyl), 123.9 (CH, C-5', Triazole), 123.9 (CH, C-2, Phenyl), 124.7 (CH, C-6, Phenyl), 130.7 (CH, C-6'', Benzyl), 130.8 (CH, C-5'', Benzyl), 132.8 (C, C-1, Phenyl), 138.5 (C, C-1'', Benzyl), 143.1 (C, C-4', Triazole), 153.6 (C, C-4, Phenyl), 160.8 (C, C-3'', Benzyl), 163.3 (C=O, NH-CO-CH3).IR (ATR) cm-1, ν: 825(Para Substituted Benzene), 1013(C-O, Phenol), 1176(C-C, Aliphatic), 1245 (C-F), 1383 (C-H, (B) Aliphatic), 1559 (C=C, Aromatic), 1663 (C=O, Amide), 2874 (C-H, Aliphatic), 2930(C-H, Aromatic), 3290(N-H, Amide).
MS (ESI) m/z: 341 [M+1], C18H17FN4O2.
"N-(4-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide"(7h)
Yellow solid,60% yield.
mp: 187-189°C.
"1H -NMR (400 MHz, DMSO) δ: 2.00 (3H, s, NH-CO-CH3), 5.11 (2H, s, C6H5-CH2)", 5.80 (2H, s, O-CH2), 6.95 (2H, d, J=8.7 Hz, H-3,5 (Phenyl)), 7.50 (4H, dd, J=8.7, 9.2 Hz, H-5' (Triazole), H-2", 6" (Benzyl)), H-2 (Phenyl)), 8.24 (2H, d, J=8.7 Hz, H-6 (Phenyl), NH-CO-CH3), 8.33 (1H, s, H-3"(Benzyl)), 9.78 (1H, s, H-5"(Benzyl)).
13C-NMR (400 MHz, DMSO) δ: 23.7 (CH3, NH-CO-CH3), 51.9 (CH2, C6H5-CH2), 61.2 (CH2, O-CH2), 114.7 (CH, C-3, C-5, Phenyl), 120.4 (CH, C-5', Triazole), 123.8 (CH, C-3'', C-5'', Benzyl), 125.0 (CH, C-2, C-6, Phenyl), 128.9 (CH, C-2'', C-6'', Benzyl), 132.9 (C, C-1, Phenyl), 143.3 (C, C-4', Triazole), 143.3 (C, C-1'', Benzyl), 147.2 (C, C-4'', Benzyl), 153.6 (C, C-4, Phenyl), 167.7 (C=O, NH-CO-CH3).IR (ATR) cm-1, ν: 825(Para Substituted Benzene), 1013 (C-O, Phenol), 1176 (C-C, Aliphatic), 1383 (N-O Stretch), 1410 (C-H, (B) Aliphatic), 1559 (C=C, Aromatic), 1663 (C=O, Amide), 2874 (C-H, Aliphatic), 3091 (C-H, Aromatic), 3290 (N-H, Amide).
MS (ESI) m/z: 368 [M+1], C18H17N5O4.
, Claims:5. CLAIMS
I/We Claim:
1. A Compositions of paracetamol embedded [1, 2, 3]-triazoles wherein, the two pharmacophores i.e. Paracetamol and Triazoles are combined to form Paracetamol embedded [1,2,3]-triazole derivativesby click chemistry approach, wherein the compound and their derivatives are given as:
S.no. Comp. Structure Name
1. 7a
N-(4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
2. 7b
N-(4-((1-(3-methyl benzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
3. 7c
N-(4-((1-(4-methyl benzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
4. 7d
N-(4-((1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
5. 7e
N-(4-((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
6. 7f
N-(4-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
7. 7g
N-(4-((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
8. 7h
N-(4-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide
2. The Compositions of paracetamol embedded [1, 2, 3]-triazole, as claimed in claim 1, wherein, the method of preparation of the compounds is given by:
a. STEP-1: Synthesis of Propargylated Paracetamol (6a):
i. Under nitrogen atmosphere, 5 mmol of Paracetamol was added to 8mL of Di methyl Formamide and then after add 10 mmol of Potassium carbonate and 5 mmol of Propargyl bromide.
ii. The resulting reaction mixture was stirred for 12 hours at room temparature and completion of reaction was monitored by thin layer chromatography.
iii. After completion of reaction, add ice, citric acid and stir the mixture again for 1 hour.
iv. The product was filtered, dried and subjected to column chromatography for purification."
b. STEP-2: Synthesis of Aryl Alcohols (2a-h):
i. Under nitrogen atmosphere 5.9 mmol of Aryl Aldehyde (1a-h) was added to 10 mL of Methanol and then add 24 mmol of Sodium borohydride.
ii.The resulting reaction mixture was stirred at 0°c for 2 hours and reaction was monitored by thin layer chromatography.
iii.Methanol was evaporated then the residue was added to EtOAc and water mixture.
iv.The Ethyl acetate layer was collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification.
c. STEP-3: Synthesis of Alkyl Bromides (3a-h):
i. Under nitrogen atmosphere, 1 g of Aryl Alcohol (2a-h) was added to 10 mL of Ether and then add 0.5 equiv of Phosphorus tribromide.
ii. The resulting reaction mixture was stirred at 0 °C for 0.5 hours and then after the residue was added to EtOAc and water mixture.
iii. The Ethyl acetate layer was collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification.
d. STEP-4: Synthesis of Alkyl Azides (4a-h):
i. Under nitrogen atmosphere, 2 equiv of Sodium azide and Tetrabutylammonium bromide was added to a solution of Alkyl halide (3a-h) (1 g) in 4:8 aqueous Dichloromethane.
ii. The resulting reaction mixture was stirred for 12 hours at room temperature and then after the residue was added to Dichloromethane and water mixture.
iii. The Dichloromethane layer was collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification.
e. STEP-5: Synthesis of Paracetamol embedded [1,2,3]-triazole derivatives by using CLICK CHEMISTRY Approach (7a-h):
i. Under nitrogen atmosphere, 1 g of (N-(3-(prop-2-ynyloxy)phenyl) acetamide (6a) was added to 7:8 aqueous THF(Tetrahydrofuran) then add 1.1 equiv of azide (4a-h), 200 mg of sodium ascorbate and 0.25 mmol of copper sulphate pentahydrate.
ii. The resulting reaction mixture was stirred for 8 hours at room temperature and then after the residue was added to Ethyl acetate and water mixture.
iii. The Ethyl acetate layer was collected and dried using anhydrous sodium sulfate then subjected to column chromatography for purification.
Documents
Name | Date |
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202441087377-COMPLETE SPECIFICATION [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-DRAWINGS [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-EDUCATIONAL INSTITUTION(S) [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-EVIDENCE FOR REGISTRATION UNDER SSI [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-EVIDENCE FOR REGISTRATION UNDER SSI(FORM-28) [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-FORM 1 [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-FORM 18 [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-FORM FOR SMALL ENTITY(FORM-28) [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-FORM-9 [13-11-2024(online)].pdf | 13/11/2024 |
202441087377-REQUEST FOR EARLY PUBLICATION(FORM-9) [13-11-2024(online)].pdf | 13/11/2024 |
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