morpholine

Morpholine is a heterocyclic secondary amine. It is formed by the condensation of diethanolamine and sulfuric acid.^[1] Its IR spectra and Raman spectra at -180°C has been recorded^[2]. The crystal structure of morpholine has been determined at 150K.^[3] The microwave spectra of morpholine within the 8 to 40GHz region have been investigated.^[4] Ascorbate anion and glutathione have been reported to inhibit the aqueous reaction between nitrogen dioxide and morpholine.^[5] Conformational studies by Raman spectroscopy and theoretical calculations suggest that equatorial chair conformation of morpholine predominates in the pure liquid state. Degradation of morpholine using Mycobacterium sp. strain RP1 has been proposed.

Figure 1 the chemical structure of morpholine
Morpholine is an organic chemical compound (O(CH2CH2)2NH) containing nitrogen and oxygen heterocyclic six membered ringand is considered important building blocks in the field of medicinal chemistry field^[8-10]. The parent compound morpholine or 1-oxa-4-azacyclohexane has become commercially available in USA in 1935; since that time, it becomes one of the most widely used heterocyclic secondary amines. Morpholine derivatives are very essential in the drug discovery process and stimulate research in broad spectrum of biological activity study^[11]. This class of heterocyclic compounds; have found great significance in modern years due to their variety of pharmacological activities including analgesic, anti-inflammatory, anticancer, antidepressant, HIV-protease inhibitors, appetite suppressant, local anaesthetic, antiplatelet, selective inhibitor of protein kinase C, antitumor, neuroprotective, antifungal, anti-tuberculosis, anti-parasitic, anti-malarial, hypolipidemic and hypocholesterolemic activities^[12-16].

Morpholine is suitable for use as a test compound in the study of morpholine biodegradation by Mycobacterium strains.^[6]
It may be used in the following cases: As a reactant in the synthesis of 1,3-dihydro-1-hydroxy-3-morpholin-4-yl-2, 1-benzoxaborole by reacting with o-formylphenylboronic acid.^[3] As a corrosion inhibitor and to maintain basic pH in boiler feed water.^[3]; As a reactant in the bis-(β-ketoenolates) nickel(II) adducts of morpholine.^[3]; As one of the reagent used in the colorimetric quantitative determination of C-2 unsubstituted phenothiazine derivatives.^[4]; As a reactant in the quantitative determination of α, β-unsaturated compounds.^[5].
Morpholine is also used as selective inhibitors of cytochrome p450 2a13 in treatment of cancer. Morpholine is a building block in the preparation of the antibiotic Linezolid, the anticancer agent gefitiniband the analgetic dextromoramide.

Morpholine is a fairly strong base (pKa 8.7, lower than that of piperidine) and potent solvent and is widely used in industry and organic synthesis^[17]. It is often selected as starting material for the preparation of enantiomerically pure α-amino acids^{[10, 11]}, βamino alcohols^[18], peptides^[19], as well as building blocks for the synthesis of biologically active compounds^[20]. Various functionalized morpholine occur in nature. Some synthetic biologically active compounds containing a morpholine ring are used in medical practice.
These classes of compounds have been utilized extensively by the pharmaceutical industry in drug design, because of the development in pharmacokinetic properties that it can bestow. The pharmacological utility of lead molecules containing the morpholine entity is widespread, particularly; N-substituted morpholines are drug molecules with a broad spectrum of pharmacological activities. The Linezolid^[14] antibiotic having a morpholine cycle is commercially available antimicrobial agent. Aprepitantis a substance that is neurokinin 1 (NK1) receptor antagonist and it is the first drug approved by Food and Drug Administration for the management of vomiting and chemotherapy-induced nausea. Former molecules displayed an antischizophrenic activity via interaction with the N-methyl-D-aspartate receptor in the brain. A selective inhibitor of epidermal growth factor Timolol (non-selective beta-adrenergic receptor antagonist indicated for treating glaucoma) Moclobemide^[22], Emorfazone (anti-inflammatory drug and analgesic)^[23], Phenadoxone (Heptalgin, opioid analgesic), anti-depressants Reboxetine^[24] and Gefitinib^[25], appetite suppressants Phenmetrazine (Preludin, 3-methyl-2-phenylmorpholine) and 2-benzylmorpholine and Canertinib, Fenpropimorph (R = 4-t-BuC6H4; fungicide)[26], and antibacterial drugs Finafloxacin , Levofloxacin^[27].
Several enzyme inhibitors as well as various receptor antagonists and agonists are well known along with morpholine-containing derivatives. Selective norepinephrine inhibitors (antidepressants)^[28], HER (Human Epidermal Growth Factor Receptor) kinase inhibitors, glucosidase inhibitors^[29], P38 MAP kinase inhibitors, PI3K kinase inhibitors (used in tumor chemotherapy), phosphoinositide 3-kinase inhibitors, FLT3 (thirosine) kinase inhibitors, urease inhibitors, cysteine protease inhibitors, selective SV2 receptor agonists, D-dopamine receptor agonists, 5-lipoxygenase inhibitors (5-LO), V3 vasopressin receptor antagonists, σ receptor antagonists, nicotine acetylcholine receptor antagonist HL-60, A431, HS27, HEP-G2, HT29, KV, K562 human cancer cell growth inhibitors and neuropeptide NPY-Y5 receptor antagonists, and antiviral, analgesic, antibacterial, anti-inflammatory agents and anticonvulsants were described^[30-33]. Morpholines have also found applications as catalysts and ligands in asymmetric addition of organo-zinc compounds to aldehydes^[34], amides (synthesis of γ-lactones, synthesis of δ-lactones & lactams) and cyclization of enals with ketones^[35], aldolization, indoles with unsaturated aldehydes, alkylation of Heck cross-coupling of aryl halides with alkenes, Michael addition of α, β-unsaturated aldehydes to 1,3-diketones, Buchwald–Hartwig amination of (hetero) aryl chlorides. Numerous morpholine derivatives are now commercially existing e.g., 4-(4, 6-dimethoxy1,3,5-triazin-2-yl)-methylmorpholinehydrochloride (DMTMM) has been extensively used in the current years in the synthesis of carboxylic acid amides and esters, N-Methylmorpholine-N-oxide (NMO) is used as co-oxidant and highly polar solvent^[36].

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