99108-56-2

Usage

Uses

Used in Medicinal Chemistry:
Morpholine is used as a building block in the synthesis of various pharmaceutical compounds, including the antibiotic Linezolid, the anticancer agent Gefitinib, and the analgesic Dextromoramide. It is also used as a selective inhibitor of cytochrome P450 2A13 in cancer treatment.
Used in Chemical Synthesis:
Morpholine is used 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. It is also used as a reactant in the bis-(β-ketoenolates) nickel(II) adducts of morpholine and in the quantitative determination of α, β-unsaturated compounds.
Used in Industrial Applications:
Morpholine is used as a corrosion inhibitor and to maintain basic pH in boiler feed water. It is also used as one of the reagents in the colorimetric quantitative determination of C-2 unsubstituted phenothiazine derivatives.
Used in Environmental Studies:
Morpholine is suitable for use as a test compound in the study of morpholine biodegradation by Mycobacterium strains.

Pharmaceutical application

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].

References

Parkin, A, I. D. Oswald, and S. Parsons. "Structures of piperazine, piperidine and morpholine." Acta Crystallographica 60.2(2010):219-227. R.V. Cooney, P.D. Ross, and G.L. Bartolini. "N -nitrosation and N -nitration of morpholine by nitrogen dioxide: Inhibition by ascorbate, glutathione and α-tocopherol." Cancer Letters 32.1(1986):83-90. El-Shabouri, S. R., et al. "Colorimetric determination of C-2 unsubstituted phenothiazines, using morpholine and N-bromosuccinimide. " Journal Association of Official Analytical Chemists69.69(1986):821-824. Poupin P, et al. "Degradation of morpholine by an environmental Mycobacterium strain involves a cytochrome P-450. " Applied and Environmental Microbiology 64.1(1998):159-165. De, Muynck L, et al. "The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding." Neurobiology of Aging 34.11(2013):2541-2547. Combourieu, B, et al. "Common degradative pathways of morpholine, thiomorpholine, and piperidine by Mycobacterium aurum MO1: evidence from (1)H-nuclear magnetic resonance and ionspray mass spectrometry performed directly on the incubation medium." Applied & Environmental Microbiology 66.8(2000):3187. https://www.trc-canada.com/product-detail/?CatNum=M723725&CAS=110-91-8&Chemical_Name=Morpholine&Mol_Formula=C?H?NO Review of morpholine and its derivatives, Merck Index, 12th ed. published by Merck & co, Whitehouse Station, NJ, 1996; 1074-5. Pushpak, M.; Bekington, M. Synthesis of substitute 4-(3-alkyl-1,2,4-oxadiazol-5ylmethyl)-3,4-dihydro-2H-1,4benzoxazinesand 4-(1H-benzimidazol-2-ylmethyl)-3,4-dihydro-2H-1,4benzoxazines. Tetrahedron Lett. 2006; 47(44):7823-7826. Zhou, G.; Zorn, N.; Ting, P.; Aslanian, R.; Lin M.; Cook John. Development of Nove benzomorpholine class of diacylglycerol acyltransferase I inhibitors. Med. Chem. Lett. 2014; 5(5): 544-549. Achari, B.; Sukhendu, B.M.; Dutta, P.; Chowdhury, C.; Perspectives on 1, 4-benzodioxions,1, 4-benzoxazines and their 2, 3dihydro derivatives. Synlett. 2004; 14:2449-2467. Panneerselvam, P.; Pradeepchandran, R.V.; Sreedhar,S.K. Synthesis, characterization and biological activities of novel 2-methyl-quinazolin-4(3H)-ones. Indian J. pharm. Sci. 2003; 65(3): 268-273. Brown, G.R.; Foubister, A.J &Stribling D. Synthesis and resolution of 3-substituted morpholine appetite suppressants and chiral synthesis via o-arylhomoserines. J. Chem. Soc. Perkin Trans. 1987; 1: 547. El-masry, A.H.; Fahmy, H.H.;Abdelwahed, A. S..H.Synthesis and Antimicrobial Activity of Some New Benzimidazole Derivatives. Molecules.2000; 12:1429. Duhalde, V.; Lahillie, B.; Camou, F.; Pedeboscq, S.; Pometan, J.P; Proper use of antibiotics: Aprospective study on the use of linezolid in a French university hospital. Pathologie. Biologie. 2007; 55(10): 478-481. Marireau, C.; Guilloton, M.; kartst, F. In vivo effects of fenpropimorph on the yeast Saccharomyces cerevisiae and determination of the molecular basis of the antifungal property. Antimicrob Agents Chemother.1990; 34(6): 989-993. Sawargave, S.P.; Kudale, A.S.; Deore, J.V.; Bhosale, D.S, Divse, J.M; Chavan, S.P; & Borate, H.B. One-step synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines and their use in the synthesis of highly functionalized 2,3,5,6,7and 2,3,4,5,7-substituted indoles. Tetrahedron Lett 2011; 52: 5491. Segat-Dioury, F.; Lingibé, O.; Graffe, B.; Sacquet M-C.; Lhommet G. A General Synthesis of enantiopure 1,2-aminoalcohols via chiral morpholinones. Tetrahedron 2000; 56: 233-248. Trabocchi, A.; Krachmalnicoff, A.; Menchi, G.; Guarna, A.;Synthesis and conformational studies of a hybrid β-alanine-morpholine tetramer, Tetrahedron, 2012; 68: 9701. Walker DP, Eklov BM., Bedore, M.W.,Practical Synthesis of 3-Oxa-6-azabicyclo[3.1.1]heptane hydrotosylate; A novel morpholine-based building block, synthesis, 2012; 44: 2859. Tosi, G.; Zironi, F.; Caselli, E.; Forni, A.; and Prati, F.; Biocatalytic asymmetric synthesis of (S)and timolol, Synthesis, 2004; 1625. Shvaika, OL.;Osnovisintezul?kars ’kikhrechovin (Principles of Synthesis of Medicines), Donets’k: Skh?dniiVidavn. D?m, 2002. Assaf, G.; Cansell, G.; Critcher, D.; Field, S.; Hayes, S.; Mathew, S.; and Pettman, A. application of a process friendly morpholine synthesis to ( S, S)-Reboxetine, Tetrahedron Lett., 2010; 51: 5048. Hanlon, S.P.; Camattari, A.; Abad, S.; Glieder, A.; Kittelmann, M., Lu?tz, S.; Wirz, B.; and Winkler, M.; Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis, Chem. Commun., 2012; 48: 6001. Tatsumi, Y.; Yokoo, M.; Senda, H.; and Kakehi, K. Therapeutic efficacy of topically applied KP-103 against experimental tinea unguium in guinea pigs in comparison with amorolfine and terbinafine.Antimicrob. Agents Chemother.,2002; 46: 3797. D.S. and Li, J.J.; Eds.; Hoboken, N.J. The Art of Drug Synthesis, Johnson,: Wiley, Canada, 2007, 71-81. Yang, Q.; Ulysse, L.G.; McLaws, M.D.; Keefe, D.K.; Haney, B.P.; Zha, C.; Guzzo, P.R.; and Liu, S. Palladium-catalyzed α-arylation reactions in total synthesis., Org. Process Res. Dev., 2012; 16: 499. Burland, P.A.; Osborn, HMI.;Turkson, A. Synthesis and glycosidase inhibitory profiles of functionalised morpholines and oxazepanes, Bioorg. Med. Chem., 2011; 19: 5679. Keldenich, J.; Michon, C.; Nowicki, A.; and AgbossouNiedercorn, F. Synthesis of a chiral key intermediate of neurokinin antagonist SSR 240600 by asymmetric allylic alkylation. Synlett, 2011; 2939. Meìtro, T.-X.; Cochi, A.; Pardo, DG.; and Cossy, J. Asymmetric synthesis of an antagonist of neurokinin receptors: SSR 241586. J. Org. Chem., 2011; 76: 2594. Lukas, R.J.; Muresan, A.Z.; Damaj, M.I.; Blough, B.E.; Huang, X.; Navarro, H.A.; Mascarella, SW.; Eaton, JB.; Marxer-Miller, SK.; Carroll, FI. Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J. Med. Chem., 2010; 53: 4731. Sun, X.; Niu, L.; Li, X.; Lu, X.; Li, F. Characterization of metabolic profile of mosapride citrate in rat and identification of two new metabolites: Mosapride N-oxide and morpholine ring-opened mosapride by UPLC-ESI-MS/MS. J. Pharm. Biomed. Anal., 2009; 50: 27. Dave, R. and Sasaki, N.A. β-Amino alcohols derived from (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine as catalysts in the asymmetric addition of diethylzinc to aldehydes, Tetrahedron: Asymmetry, 2006; 17: 388. Raup, D.E.A.; Cardinal-David, B.; Holte, D.; Scheidt, KA. Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to gamma-lactams. Nat. Chem., 2010; 2: 766. R.M, An introduction to the chemistry of heterocyclic compound 2ndedn. John wiley& sons, Inc compounds. 1976, 348. Schmidt, A.K.C.; Stark, CBW.Tetrapropylammoniumperruthenatecatalyzed glycol cleavage to carboxylic (di)acids, Org. Lett., 2011; 13: 5788.

Upstream product

• 7146-67-0 N-tosyldiethanolamine 
• 39242-76-7 4-(2,4-dinitrophenyl)morpholine 
• 111-42-2 2,2'-iminobis[ethanol] 
• 111-44-4 3-oxa-1,5-dichloropentane 
• 18502-80-2 1,2-dimorpholino-1-phenyl ethane 
• 4432-43-3 N-hydroxymethylmorpholine 
• 56176-55-7 1-morpholino-1-butene 
• 4394-85-8 4-morpholinecarboxaldehyde 
• 25070-73-9 benzyl morpholine-4-carboxylate 
• 59-89-2 N-nitrosomorpholine 
• 123-73-9 trans-Crotonaldehyde 
• 82737-08-4 N-(phenylselanyl)morpholine 
• 20830-11-9 (morpholin-4-yl-phenyl-methyl)-malononitrile 
• 98700-38-0 4-[3-(4-Fluoro-phenyl)-5-methylene-4,5-dihydro-3H-[1,2,3]triazol-4-yl]-morpholine 

Downstream Products

• 100887-18-1 4-(4-bromo-phenyl)-2-morpholino-4-oxo-butyronitrile 
• 74875-25-5 3,5-dichloro-4-N-morpholinylnitrobenzene 
• 112819-90-6 2-methylsulfanyl-3-(3-morpholino-propyl)-5,5-diphenyl-3,5-dihydro-imidazol-4-one 
• 99359-48-5 2-bromo-5-morpholino-4-nitro-aniline 
• 109257-62-7 (morpholine-4-carboximidoyl)-(toluene-4-sulfonyl)-amine 
• 114004-60-3 morpholino-acetic acid-(4-ethoxy-3-piperidinomethyl-anilide) 
• 109651-41-4 (morpholine-4-carboximidoyl)-(N-phenyl-morpholine-4-carboximidoyl)-amine 
• 120794-37-8 4-{3-[4-(6-propyl-benzo[1,3]dioxol-5-ylmethyl)-phenyl]-propyl}-morpholine 
• 101879-16-7 benzoic acid-(3-morpholino-4-nitro-anilide) 
• 109721-93-9 morpholine-4-carboxylic acid-[4-(2-morpholino-ethoxy)-anilide] 
• 21546-33-8 4-amino-2-hydroxy-benzoic acid 2-morpholin-4-yl-ethyl ester 
• 107379-41-9 N-(3-morpholino-4-oxo-4H-[1]naphthylidene)-benzenesulfonamide 
• 94916-79-7 5-benzyloxy-3-(2-morpholin-4-yl-ethyl)-indole 
• 111638-87-0 3,3'-Dimethoxy-4,4'-bis-(2-morpholino-acetylamino)-biphenyl 

Relevant academic research and scientific papers

The benzyl can be selectively removed by visible light or near visible light. Method for protecting allyl and propargyl group

The invention provides a method for selectively removing benzyl, allyl and propargyl protecting groups by visible light or near visible light, namely a substrate containing benzyl, allyl or propargyl protecting groups. The method has the advantages of simple operation, safe and clean visible light or near visible light as excitation conditions, cheap and easily available reagents, high reaction yield, high reaction chemistry and regional selectivity, and is suitable for selective removal of benzyl, allyl and propargyl protecting groups in various substrates.

A Lewis Base Nucleofugality Parameter, NFB, and Its Application in an Analysis of MIDA-Boronate Hydrolysis Kinetics

The kinetics of quinuclidine displacement of BH3 from a wide range of Lewis base borane adducts have been measured. Parameterization of these rates has enabled the development of a nucleofugality scale (NFB), shown to quantify and predict the leaving group ability of a range of other Lewis bases. Additivity observed across a number of series R′3-nRnX (X = P, N; R′ = aryl, alkyl) has allowed the formulation of related substituent parameters (nfPB, nfAB), providing a means of calculating NFB values for a range of Lewis bases that extends far beyond those experimentally derived. The utility of the nucleofugality parameter is explored by the correlation of the substituent parameter nfPB with the hydrolyses rates of a series of alkyl and aryl MIDA boronates under neutral conditions. This has allowed the identification of MIDA boronates with heteroatoms proximal to the reacting center, showing unusual kinetic lability or stability to hydrolysis.

Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.

Discovery and characterization of an acridine radical photoreductant

Photoinduced electron transfer (PET) is a phenomenon whereby the absorption of light by a chemical species provides an energetic driving force for an electron-transfer reaction1–4. This mechanism is relevant in many areas of chemistry, including the study of natural and artificial photosynthesis, photovoltaics and photosensitive materials. In recent years, research in the area of photoredox catalysis has enabled the use of PET for the catalytic generation of both neutral and charged organic free-radical species. These technologies have enabled previously inaccessible chemical transformations and have been widely used in both academic and industrial settings. Such reactions are often catalysed by visible-light-absorbing organic molecules or transition-metal complexes of ruthenium, iridium, chromium or copper5,6. Although various closed-shell organic molecules have been shown to behave as competent electron-transfer catalysts in photoredox reactions, there are only limited reports of PET reactions involving neutral organic radicals as excited-state donors or acceptors. This is unsurprising because the lifetimes of doublet excited states of neutral organic radicals are typically several orders of magnitude shorter than the singlet lifetimes of known transition-metal photoredox catalysts7–11. Here we document the discovery, characterization and reactivity of a neutral acridine radical with a maximum excited-state oxidation potential of ?3.36 volts versus a saturated calomel electrode, which is similarly reducing to elemental lithium, making this radical one of the most potent chemical reductants reported12. Spectroscopic, computational and chemical studies indicate that the formation of a twisted intramolecular charge-transfer species enables the population of higher-energy doublet excited states, leading to the observed potent photoreducing behaviour. We demonstrate that this catalytically generated PET catalyst facilitates several chemical reactions that typically require alkali metal reductants and can be used in other organic transformations that require dissolving metal reductants.

Rational selection of co-catalysts for the deaminative hydrogenation of amides

The catalytic hydrogenation of amides is an atom economical method to synthesize amines. Previously, it was serendipitously discovered that the combination of a secondary amide co-catalyst with (iPrPNP)Fe(H)(CO) (iPrPNP = N[CH2CH2(PiPr2)]2-), results in a highly active base metal system for deaminative amide hydrogenation. Here, we use DFT to develop an improved co-catalyst for amide hydrogenation. Initially, we computationally evaluated the ability of a series of co-catalysts to accelerate the turnover-limiting proton transfer during C-N bond cleavage and poison the (iPrPNP)Fe(H)(CO) catalyst through a side reaction. TBD (triazabicyclodecene) was identified as the leading co-catalyst. It was experimentally confirmed that when TBD is combined with (iPrPNP)Fe(H)(CO) a remarkably active system for amide hydrogenation is generated. TBD also enhances the activity of other catalysts for amide hydrogenation and our results provide guidelines for the rational design of future co-catalysts.

Selective Room-Temperature Hydrogenation of Amides to Amines and Alcohols Catalyzed by a Ruthenium Pincer Complex and Mechanistic Insight

We report a room-temperature protocol for the hydrogenation of various amides to produce amines and alcohols. Compared with most previous reports for this transformation, which use high temperatures (typically, 100-200 °C) and H2 pressures (10-100 bar), this system proceeds under extremely mild conditions (RT, 5-10 bar of H2). The hydrogenation is catalyzed by well-defined ruthenium-PNNH pincer complexes (0.5 mol %) with potential dual modes of metal-ligand cooperation. An unusual Ru-amidate complex was formed and crystallographically characterized. Mechanistic investigations indicate that the room-temperature hydrogenation proceeds predominantly via the Ru-N amido/amine metal-ligand cooperation.

Practical Synthesis of Phosphinic Amides/Phosphoramidates through Catalytic Oxidative Coupling of Amines and P(O)?H Compounds

Herein, we report a highly efficient ZnI2-triggered oxidative cross-coupling reaction of P(O)?H compounds and amines. This operationally simple protocol provides unprecedented generic access to phosphinic amides/phosphoramidate derivatives in good yields and short reaction time. Besides, the reaction proceeds under mild conditions, which avoids the use of hazardous reagents, and is applicable to scale-up syntheses as well as late-stage functionalization of drug molecules. The stereospecific coupling is also achieved from readily available optically enriched P(O)?H compounds.

Catalytic Hydrogenation of Thioesters, Thiocarbamates, and Thioamides

Direct hydrogenation of thioesters with H2 provides a facile and waste-free method to access alcohols and thiols. However, no report of this reaction is documented, possibly because of the incompatibility of the generated thiol with typical hydrogenation catalysts. Here, we report an efficient and selective hydrogenation of thioesters. The reaction is catalyzed by an acridine-based ruthenium complex without additives. Various thioesters were fully hydrogenated to the corresponding alcohols and thiols with excellent tolerance for amide, ester, and carboxylic acid groups. Thiocarbamates and thioamides also undergo hydrogenation under similar conditions, substantially extending the application of hydrogenation of organosulfur compounds.

Palladium doping of In2O3 towards a general and selective catalytic hydrogenation of amides to amines and alcohols

Herein, the first general heterogeneous catalytic protocol for the hydrogenation of primary, secondary and tertiary amides to their corresponding amines and alcohols is described. Advantageously, this catalytic protocol works under additive-free conditions and is compatible with the presence of aromatic rings, which are fully retained in the final products. This hydrogenative C-N bond cleavage methodology is catalyzed by a Pd-doped In2O3 catalyst prepared by a microwave hydrothermal-assisted method followed by calcination. This catalyst displays highly dispersed Pd2+ ionic species in the oxide matrix of In2O3 that have appeared to be essential for its high catalytic performance.

Sodium Triethylborohydride-Catalyzed Controlled Reduction of Unactivated Amides to Secondary or Tertiary Amines

The first transition-metal-free catalytic protocol for controlled reduction of amide functions using cheap and bench-stable hydrosilanes as reducing agents has been established. By altering the hydrosilane and solvent, the new method enables the selective cleavage of unactivated C-O bonds in amides and allows the C-N bonds to selectively break via the deacylated cleavage. Overall, this novel process may offer a versatile alternative to current methodologies employing stoichiometric metal systems for the controlled reduction of carboxamides.