Morpholine-amide derivative

Morpholine-amide derivative 55 was rapidly considered as a preclinical candidate due to a well-balanced profile and advantageous comparison with compound 53 on a number of parameters (Figure 18.18). 

For an improved procedure with amides, see Olah, G.S. Prakash, G.K.S. Arvanaghi, M. Synthesis, 1984, 228. See Martin, R. Romea, R Tey, C. Urpi, R Vilarrasa, J. Synlett, 1997, 1414 for reaction with an amide derived from morpholine and Grignard reagents, whch gives the ketone in good yield. See Kashima, C. Kita, I. Takahashi, K. Hosomi, A. J. Heterocyclic Chem., 1995, 32, 25 for a related reaction. 

Ketones, including chiral a-amino ketone derivatives, are also produced from the organolithium reaction with morpholine amides. 

Similarly, a-trichloromethylamines (522) were obtained by decomposition of trichloroacetic acid in morpholine enamines, but an amide ester was formed from sodium trichloroacetate and the imonium salt of pyrrolidino-cyclohexene (523). The product is presumably derived from opening of an intermediate dichloroaziridinium salt. 

Yet another nontricyclic antidepressant consists of a relatively simple morpholine derivative. Acylation of aziridine with p-chlorobenzoyl chloride gives the amide 130. This intermediate is. sufficiently reactive to undergo ring opening on treatment with morpholine. The product is the antidepressant agent moclobemide (131) 33J. 

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... 

In the carbonylation reactions, further reaction of the acyl lithium compounds with carbon monoxide can occur, but clean reaction can be achieved if the lithium amide is first converted to a copper derivative (Scheme 130) (79JOC3734). In the case of morpholine, reaction with allyl bromide gave a 93% overall yield of the amide product. 

Another important line of research was the synthesis of 3,4,5-trialkoxybenzamides, as some of these derivatives showed outstanding psychopharmacological activities. Among these compounds, 4-(3,4,5-trimethoxybenzoyl)morpholine (named Trioxazin) was introduced as a minor tranquilizer, N-cyclopropyl-4-(decyloxy)-3,5-dimethoxybenz-amide (Denegit) as an antiepileptic agent, and 2-(l-pyrrolidinyl)ethyl 4-butoxy-3,5-dimethoxybenzoate (Vasopenton) as a spasmolytic, for use in clinical practice. 

The morpholine derivative 75 has an obvious amide disconnection to 76 and a less obvious 1,2-diX disconnection at the ether to 77. This is obviously an epoxide 78 adduct with ammonia. 

The reaction is a two-stage reaction with the initial formation of the alkanolamine soap followed by dehydration to form the alkanolamide. At the same time, significant quantities of amine esters and amide esters are formed by the side reaction. If a dialkanolamine is used as the starting material, smaller amounts of amine diester and amide diester are formed as well as some morpholine and piperazine derivatives. 

Metabolites derived by loss of an alkyl or arylalkyl group from ethers [Eq. (4)], thioethers [Eq. (5)], amines [Eq. (6)], and amides [Eq. (7)] represent common biotransformation pathways (R, R" = H, alkyl or aryl). These processes involve oxidation on carbon adjacent to the heteroatom. The intermediates are generally unstable and readily decompose to the corresponding alcohol, thiol, amine, or amide and an aldehyde. Intermediates formed from amides [Eq. (7)] are more stable and may be detected as excreted metabolites. If a secondary carbon atom is adjacent to the heteroatom, then this portion of the molecule is released as a ketone. The heteroatom may also be located in a cyclic structure (e.g., morpholine, piperazine). Two processes have been adopted for amines, namely, N-dealkylation or deamination, that are essentially the same event. In general, which of the two terms applies depends on the... 

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