Aminoalcohol ethers

Compounds 13-15 are tertiary aminoalcohol ethers, a type of structure typically associated with the early antihistamines such as diphenhydramine. It is known that one of the most prominent and annoying side effects of such drugs (dryness of the mouth) are effects associated with anticholinergic mechanisms. In fact, this property has led to its use in Parkinsonism and particularly for drug-induced extrapyramidal movement disorders. The o-methyl analog, orphenadrine, was introduced because of its lower antihistaminic activity and higher anticholinergic action. Because it also reduces spasticity in voluntary muscles it is marketed as a skeletal muscle relaxant as well (under a different trade name). 

Generally, the aminoalcohol ethers have been more widely employed as anti-parkinsonism agents rather than as usual antimuscarinic drugs. A few sueh eompounds, namely benztropine mesylate, chlorphenoxamine hydrochloride and orphenadrine citrate have been adequately discussed under anti-parkinsonism drugs. 

Similarly, lipase-catalyzed kinetic resolution has also been applied to intermediate nitrile alcohol 46 (Scheme 14.14). Best results were obtained by using immobilized Pseudomonas cepacia (PS-D) in diisopropyl ether, leading to excellent yield and enantiomeric excess of the desired (5)-alcohol 46a, along with (/J)-nitrile ester 47. Reduction of 46a with borane-dimethylsulhde complex, followed by conversion to the corresponding carbamate and subsequent lithium aluminum hydride reduction gave rise to the desired (S)-aminoalcohol intermediate 36, a known precursor of duloxetine (3). 

Triflic acid has been used in the selective esterification ( (9-acylation) of a series of aminoalcohols in the presence of a crown ether (DB24C8) to prepare rotaxanes.900 The test reaction of diethanolamine with bulky anhydride, crown ether, and triflic acid (molar ratio = 1 2 2 1.5) gave the rotaxane 276 in high yield in a clean reaction [Eq. (5.327)]. /V-Arylmethylaminoalcohols were similarly transformed (85-92% yields). 

If you don t see at once what reagent will be used for the synthon 37, you are not alone. How can we use the other OH group at C-l to make C-2 electrophilic One way to visualise the answer is to imagine what would happen if you actually made the cation 37. It would instantly cyclise 38 to form a three-membered ring 39 that could lose a proton to give the epoxide 40. Epoxides are strained ethers and react with nucleophiles such as amines 41 to give 42 and hence the aminoalcohol 33. 

Methyl-/V-fert(butyldimethylsilyl)trifluoroacetam-ide (MTBSTFA, CAS 77377-52-7) is another common silylation reagent used for CWC-related chemicals. BSTFA silylates aminoalcohols such as triethanolamine (CAS 102-71-6) give higher recoveries than MTBSTFA, but the te/T-butyldimethylsilyl ethers formed when MTBSTFA is used are more stable than the trimethylsilyl ethers formed with BSTFA. 

Other previously described chiral allenyllithiums derived from aminoalcohols 761-764, menthol 765 and sugars 766-7681087 1,189 have been prepared by deprotonation with n-BuLi in ether at —40°C for 15 min. They reacted with carbonyl compounds giving, after hydrolysis, enantioenriched a-hydroxy ketones. 

Reaction with (172) and other aldoximes may require oxime activation, which can be achieved with the addition of 1 equiv. of BF3-OEt2." " Yields in the addition of organometallic reagents to substituted aldoximes are modest and are a function of the isomeric composition of the oxime ethers, as the (Z)-oxime isomers are reported to preferentially react with organolithium reagents (entries 1 and 2, Table 13). ° The reaction has been employed for the preparation of 6-aminoalkyl-substituted pencillins (entry 3, Table 13)."° Cyclic oxime ether additions have also been evaluated (entries 4 and 5, Table 13). ° With the lability of the nitrogen-oxygen bond, addition to S-substituted isoxazolines provides a potential avenue for stereospecific synthesis of substituted 3-aminoalcohols (entry 5, Table 13). 

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