Chiral compounds morpholines

Reboxetine is a nontricyclic SNRI in which the propylamine side chain of the TCAs is constrained into a morpholine ring (Fig. 21.8). It is a potent and selective ligand for the NET, with a mechanism of action is similar to that of desipramine. Reboxetine is used for the treatment of major depressive disorders. It is a chiral compound that is marketed as a racemic mixture of R,R- and S,S-reboxetine. The antidepressant activity for reboxetine appears to reside with the S,S-(+)-enantiomer, which has approximately twofold the inhibition potency of the R,R-enantiomer (42). It is well tolerated, with different adverse-event profiles, and it appears to be at least as effective as the SSRIs in the treatment of depressive illness. Currently, it is available only in Europe and is under U.S. FDA review. It preferentially inhibits the reuptake of NE (5-FIT NE ratio, 8). Reboxetine is not metabolized by the polymorphic isoforms, CYP2D6 or CYP2C19, and may offer a valuable alternative to the secondary amine TCAs in the treatment of major depression. Reboxetine is likely to become a promising alternative for patients who have failed treatment with or do not tolerate serotonergic antidepressants. Reboxetine has been shown to be effective and well tolerated in the treatment of panic... 

During the development of rivaroxaban 1, Pleiss et al. at Bayer Health Care prepared [14C]-radiolabeled rivaroxaban,22 which was required for clinical studies of drug absorption, distribution, metabolism, and excretion (ADME studies). The approach taken for the synthesis of l4C labeled rivaroxaban 38 relies on the previously reported synthesis. In the presence of EDC HCl and HOBT, 4- 4-[5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl -morpholin-3-one 22 was coupled with 5-chloro-2-thiophene [14C]-carboxylic acid 37 and was purified using chiral HPLC to afford the [l4C]-radiolabelled rivaroxaban 38 in 85% yield with high chemical and radiochemical purity and with an enantiomeric excess of > 99% ee (Scheme 5). Meanwhile, the metabolite M-4 of rivaroxaban (compound 39) was prepared from 5-chlorothiophenecarboxylic acid chloride 23 and [14C]glycine in 77% yield (Scheme 6). 

The antidepressant compound lubazodone (8) illustrates the breadth of the structural requirements for serotonin selective reuptake inhibitors the structure of this agent departs markedly from that of fluoxetine, the first drug in this class. The compound at hand also exemplifies the current trend for preparing drugs in chiral form. Thus reaction of the indanol (6) with the mesylate from chiral glycidic oxide in the presence of base leads to the epoxypropyl ether (7) with retention of chirality. Treatment intermediate 7 with aminoethylsulfonic acid closes the morpholine ring. Product 8 consists of pure (5) enantiomer. ... 

Other chiral morpholine derivatives containing bromine, which is readily substituted under zinc catalysis by enolates, enol ethers, and allyl compounds to give amino acids (Section D.1.4.5.) have been prepared from (1 / ,2.S )-2-amino-l,2-diphenylcthanol or its enantiomer41, both of which are available by resolution of the racemate with L-glutamic acid42 or other resolving agents (Section 2.3.2.). 

The reactions of spirocyclic phosphazenes containing a ferrocenyl substituent with morpholine afforded many products of which mono-, di-and tri- substituted ferrocenyl compounds (137)-(139) have been shown to be chiral. ... 

A method for the asymmetric hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodiazepines has recently been published. The chiral cyclic amines generated from these reactions make up the cores of many natural products and clinical drugs. Iridium-bisphosphine catalyst systems were investigated and found to give promising enantios-electivities which could be improved upon addition of morpholine tri-fluoroacetate. The optimum conditions, applied to model compound 50, are shown in Scheme 14.19, giving 51 in excellent enantioselectivity and complete conversion. 

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