Morpholine Diones

Lou et al reviewed a variety of poly(ester amide)s synthesized from morpholine-2,5-dione derivatives. Their copolymerization with LA was extensively investigated. Langer investigated the copolymerization of LA and 3-[A-(carbonylbenzoxy)-L-lysyl]-6-L-methyl-2,5-morpholinedione. And the degradability of these copolymers was enhanced regardless the deprotection of lysine residue. Feng et have reported on the enzyme-catalysed 

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The intermediate lactol was to be subjected to a diastereoselective acetalization with (/ )-3,5-bistrifluoromethylphenyl ethanol. In order to probe this diastereoselective coupling, a variety of chiral iV-R lactols 76 was desired. In addition, since the ultimate success to aprepitant via this route depended on crystalline intermediates, numerous A -substituted lactols 76 needed to be prepared in order to investigate the crystalline properties of downstream intermediates. Accordingly, a versatile procedure to access a variety of A-substituted morpholine-2,3-diones 75 and 2-hydroxymorpholin-3-ones 76 was required. This was accomplished by the condensation of amino alcohols 74 with diethyl oxalate to afford diones 75, which could be selectively reduced to the corresponding lactols 76 (Scheme 22). A host of these substrates were synthesized however, none offered any significant advantage over the simple A-Bn lactol 69. Thus, the objective became the development of a concise synthesis for this substrate. 

Adsool and Pansare coupled diastereoselective morpholine dione addition chemistry with diene RCM using [Ru]-II catalyst to generate oxocine 133 (Scheme 3.20)... 

This cydic initiator allows controlled polymerization, and is used to prepare a variety of polymeric architectures ranging from block copolymers to polymeric networks. The ROP of D,L-3-methyl-2,5-morpholmedione and 2,5-morpholine-dione with DSDOP at an monomer-to-initiator (M/I) ratio of 1000 at 130°C for 16 h gives somewhat higher polymer yields and molecular weights as compared to stannous octanoate. However, it has been found that frill control over the molecular weight via the M/I molar ratio is not possible. In addition, no reaction is observed when the polymerization is conducted with this initiator in solution... 

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

To a solution of dibenzo[6,/][l, 4]diazocine-6,l (5H. 2H)-dione (7 1.7 g, 7.5 mmol) in morpholine (10 mL) was added dropwise a cooled solution of TiClj. (3.13 g, 16.5 mmol) in anisole (10 mL). The mixture was then heated at 125 C for 2.5 h. poured into ice and extracted with CHC13. The organic layer was dried (Na2S04), concentrated in vacuo, and the residue passed through a column of neutral alumina (CHC13/ MeOH 95 5) yield 1.92 g (68 %). An analytical sample was obtained by recrystallization (CH2Cl2/ petro-leum ether) as a gray solid nip 240-243 C. 

If mono-hydroxyl functionalized polyethylene glycol), HO-PEG, is added to Ca(NTMS2)2.THF2, then addition of LA affords the diblock PEG-b-PLA (Mn= 15,500, Mn calc = 15,500, Mw/Mn = 1.03).832 Using a similar strategy the reaction of CaFI2 with telechelic diol HO-(PEG)-OH, followed by polymerization of L-LA results in a triblock structure, PLA-b-PEG-b-PLA of narrow polydispersity (1.02-1.08).835 836 Triblock copolymers of morpholine-2,5-diones with PEO have also been prepared in this manner.837... 

Initially PDPs were synthesized by stepwise polycondensation of linear activated depsipeptide [93]. In 1985, Helder, Feijen and coworkers reported the synthesis of PDPs by ROP of a morpholine-2,5-dione derivative (cyclic dimer of ot-hydroxy- and a-amino acid cyclodepsipeptide, cDP) [94, 95]. The ROP method gives an alternative type of PDP by homopolymerization and also allows the copolymerization with other monomers (lactones and cyclic diesters) including LA, GA, and CL to give a wide variety of functional biodegradable materials. The synthesis of PDPs as functional biomaterials has been recently reviewed [17]. 

The oxidation of alcohols to carbonyl compounds has been studied by several authors and a variety of methods have been used. Papers concerned vith such oxidations are illustrated (Scheme 3.26). Good results have been obtained using pyridinium chlor-ochromate (PCC) adsorbed onto silica gel for the selective oxidation of unsaturated substrates e.g. terpene [135] and furanyl derivatives [136]. Steroidal homoallylic alcohols can be converted to the corresponding 4-ene-3,6-diones using tetrapropylammo-nium per-ruthenate (TPAP) in catalytic amounts [137]. In this case, the oxidising agent is N-methyl morpholine N-oxide (NMO). 

The syntheses shown in Scheme 26 (71CB1573) are based on dibenzo-/3-tropolone (108) and its enamines. Condensation of 108 and benzoin in the presence of ammonia affords pyrrole 109. The morpholino enamine gives pyrazole 110 via benzoylation, hydrolytic elimination of morpholine, and cyclization, whereas diazo-group transfer onto the anilino enamine leads to triazole 111. Dione 108 and p-nitrophenylazide in one step give predominantly the p-nitro derivative of 111 (92G249). 

Feng Y, Klee D, Keul H, Hdcker H (2000) Lipase-catalyzed ring-opening polymerization of morpholine-2,5-dione derivatives a novel route to the synthesis of poly(ester amide)s. Macromol Chem Phys 201 2670-2675... 

Morpholine-2,5-diones have been prepared by intramolecular, nucleophilic cleavage of polystyrene-bound amino acids acylated with a-hydroxy acids (Entry 2, Table... 

This preparation is analogous to the formation of diketopiperazines from dipeptide esters. In a similar approach, morpholine-2,5-diones were obtained by acidolytic cleavage of N-(bromoacety 1)am ino acids from Wang resin (Entry 3, Table... 

Methyl-5-phenyl-pyrazol-l-yl)-benzoic Acid (27). A mixture of 4-hydrazino-benzoic acid hydrochloride (113 mg, 0.6 mmol) and morpholine-based resin (3) in MeOH (2 ml) was treated with 1-phenyl-butane-1,3-dione (81.5 mg, 0.5 mmol) and shaken for 2.5 h. The MeOH was allowed to evaporate under a stream of N2. DCM (4 ml) was then added to the reaction mixture followed by the addition of isocyanate resin (15) (350 mg). The resulting reaction mixture was shaken for 16 h at which time additional amounts of isocyanate resin (15) (120 mg) were added. The mixture was shaken for 4 h followed by filtration. The filtered resin was washed with DCM (2 x 1.5 ml). Upon concentration of the organic filtrate, clean product was obtained. MS 278.11 (M + 1). 

Heating pipecolic acids 315 in refluxing AC2O in the presence of catalytic amount of NaOAc for 1 h afforded perhydropyrido[l,2-fl]pyrazine-1,3-diones 316 (05MOL1119). The treatment of piperidine 317 with morpholine in THF at ambient temperature for 2 h afforded diketopiperazine 230 as an inseparable mixture of diastereomers (07T6124). 

Azacyclic monomers containing an endocyclic nitrogen atom which are most commonly subjected to polymerisation in the presence of coordination catalysts include a-aminoacid /V-carboxyanhydrides. However, other monomers of this type, such as morpholine-2,5-dione, have also been subjected to coordination polymerisation. 

Morpholine-2,5-dione (l,4-oxazacyclohexane-2,5-dione) is characterised by the appearance in its molecule of both the <5-lactam and -lactone functions. The coordination polymerisation of this monomer [scheme (22)] has been reported for systems with diethylzinc [178] and tin bis(ethylhexanoate) [150] as catalysts ... 

The polymer formed, poly(morpholine-2,5-dione), is a polydepsipeptide consisting of alternating sequences of a-amino acid and a-hydroxyacid (Table 9.2). 

Morpholine-2,5-dione and its substituted analogue, 6-methylmorpholine-2,5-dione, appeared to undergo copolymerisation with lactide in the presence of the zinc oxide catalyst. The copolymers obtained were characterised by an increased content of a-hydroxyacid units. The copolymerisability of the unsubstituted monomer was comparable with that of lactide. However, the N-methylated monomer was much less susceptible than the unsubstituted one to copolymerisation with lactide [178],... 

The stereochemical course of the annulation process has been determined by reaction of acryloyl chloride with the morpholine enamine of 4-f-butyl-2-methylcyclohexanone. The bicyclic dione was obtained in 76% yield as a 4 1 mixture of two isomers (Scheme 150). X-ray analysis of the main isomer showed that reaction had occurred by axial attack from the same side as the C-2 methyl group. In order for regeneration of the enamine system to occur under conditions of stereoelectronic control, the intermediate ketene-iminium salt presumably adopts a twist conformation. Cyclization of the ketene... 

No comparison between trialkyloxonium fluoroborates and dialkyl sulfates has been made, but analysis of available data shows that oxonium salts are more generally applicable reagents for the preparation of lactim ethers. The alkylation of 3-carbethoxypiperid-2-one (7)25 and morpholin-3-one (8)32 with dimethyl sulfate failed, but with triethyloxonium fluoroborate these compounds gave 2-ethoxy-3-carbethoxy-3,4,5,6-tetrahydropyridine (9) and 3-ethoxy-3,4-dehydro-morpholine (10) in excellent yield. The selective character of triethyloxonium fluoroborate is shown in its reaction with 3,3-diethyl-5-methylpiperidine-2,4-dione (11 ).25 Reaction of 11 with the calculated quantity of dimethyl sulfate resulted in alkylation of the carbonyl group in position 4 with formation of 12, but reaction of 11 with triethyloxonium fluoroborate gave the lactim ether (13). 

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