Absolute configuration of glycerol derivatives. 7. Enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]ethyl]-1,4-benzodioxane (WB-4101), a potent competitive .alpha.-adrenergic antagonist

Abstract

The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxane (4) were prepared from the chiral 2-[(tosyloxy)methyl]-1,4-benzodioxanes [(2S)- and (2R)-5]. The corresponding (2R)- and (2S)-2-(aminoethyl)-1,4-benzodioxanes [2R)- and (2S)-7] were prepared by a modified Gabriel synthesis and converted to the enantiomers of 4 by condensation with 2,6-dimethoxyphenoxyacetaldehyde (8) and reduction of the intermediate imine with NaBH4. The enantiomer (2S)-4 was 40--50 times as potent as the enantiomer (2R)-4 in antagonizing the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips, showing a pA2 = 9.0. This result is consistent with the previous observation that S enantiomers of 2-[(alkylamino)methyl]benzodioxanes are more potent antagonists at a alpha-adrenergic receptors than the R enantiomers.

Synthesis of aryloxyacetaldehydes and N-(aryloxyethyl)cyclohexanamine hydrochloroides

“…However, the yields are not high, and they rarely exceed 50%. For example, Sakurai et al [3] described the reaction of substituted phenoxyacetaldehydes with primary and secondary amine hydrochlorides in methanol in the presence of triethylamine, followed by reduction with NaBH 4 , which afforded 11-31% of the corresponding 2-phenoxyethanamines.Aryloxyacetaldehydes necessary for the synthesis of aryloxyethanamines according to [3] can also be prepared in several ways: by catalytic oxidation of 2-phenoxyethanol [7], by alkylation of phenols with bromoacetaldehyde acetals and subsequent hydrolysis [2,8], by ozonolysis of allyl phenyl ethers [9], and by oxidation of glycerol monophenyl ether with lead tetraacetate [10]. The most appropriate procedure seems to be oxidation of 2-(aryloxymethyl)oxiranes with periodic acid in aqueous medium or aqueous dioxane, which was proposed in [11] for the synthesis of phenoxyacetaldehyde.…”

“…Aryloxyacetaldehydes necessary for the synthesis of aryloxyethanamines according to [3] can also be prepared in several ways: by catalytic oxidation of 2-phenoxyethanol [7], by alkylation of phenols with bromoacetaldehyde acetals and subsequent hydrolysis [2,8], by ozonolysis of allyl phenyl ethers [9], and by oxidation of glycerol monophenyl ether with lead tetraacetate [10]. The most appropriate procedure seems to be oxidation of 2-(aryloxymethyl)oxiranes with periodic acid in aqueous medium or aqueous dioxane, which was proposed in [11] for the synthesis of phenoxyacetaldehyde.…”

“…In particular, compounds acting as local anesthetics, adrenergic neuron blocking agents [1,2], and dopamine D 2 -receptor inhibitors [3] were found among aryloxyethanamine derivatives. These compounds are commonly synthesized by alkylation of phenols with 2-halo amines [1,4] or of amines with 2-aryloxyethyl halides [4].…”

“…These compounds are commonly synthesized by alkylation of phenols with 2-halo amines [1,4] or of amines with 2-aryloxyethyl halides [4]. Also, reductive amination of aryloxyacetaldehydes with the use of sodium tetrahydridoborate [2,3,5] or hydrogen over Pd/C [6] was reported. However, the yields are not high, and they rarely exceed 50%.…”

Novel, Broad-Spectrum Anticonvulsants Containing a Sulfamide Group: Pharmacological Properties of (S)-N-[(6-Chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112)

“…12 In the case of 5 , commercially available racemic (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine was reacted with sulfamide. However, the enantiomers ( S )- 5 and ( R )- 5 were synthesized independently as above 11 from the known chiral alcohol intermediates (Method A). 12 For some derivatives of type 10 a regioselective synthesis was employed, 13 possibly with procedural modifications, to afford the single regioisomeric alcohol intermediates required.…”