Chiral synthesis of (2S,3S)‐2‐(2‐morpholin‐2‐yl‐2‐phenylmethoxy)phenol

Abstract

Resolution of (2RS,3RS)-2-[alpha-(2-methoxymethoxyphenoxy)phenylmethyl]morpholine, 11, with (+) mandelic acid led to the formation of (+)-(2S,3S)-2-[alpha-(2-methoxymethoxyphenoxy)phenyl methyl] morpholine (11a). Compound 11 was synthesized in seven steps from (2RS,3RS)-cinnamyl alcohol-2,3-epoxide (4), with an overall yield of 17%. Cleavage of the methoxymethyl group of the Fmoc derivative 12 with catalytic amounts of p-toluenesulfonic acid in methanol afforded (+)-(2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2. The synthetic utility as well as the configuration of compound 2 has been demonstrated by converting (S,S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2 to (2S,3S)-2-[alpha-(2-ethoxyphenoxy)phenylmethyl]morpholine (1) and (2S,3S)-2-(2-methoxyphenoxy) benzyl)morpholine (16), two potential norepinephrine reuptake inhibitors under clinical evaluation.

Rearrangement of β‐amino alcohols and application to the synthesis of biologically active compounds

“…(S,S)-Reboxetine is a selective norepinephrine reuptake inhibitor (NRI) which has been widely studied for its pharmacological properties. 48,49 We have to point out that the (S,S)-reboxetine has a greater affinity and selectivity for the norepinephrine transporter than its (R,R)-enantiomer 50 and different methods have been developed to access the (S,S)-enantiomer such as chemical resolution, 51,52 capillary electrophoresis, 53 chiral HPLC, [54][55][56] and asymmetric syntheses. 51,[57][58][59][60][61] As the rearrangement of linear b-amino alcohols was very selective under catalytic conditions, the synthesis of (S,S)-reboxetine was envisaged to pass through b-amino alcohol K. Rearrangement of compound K should lead to L, a known precursor of (S,S)-reboxetine (Scheme 7).…”

Synthetic Story of a Blockbuster Drug: Reboxetine, a Potent Selective Norepinephrine Reuptake Inhibitor

“…Prabhakaran and co-workers demonstrated a neat approach toward 7 via resolution of the very important scaffold 45 with (+)-mandelic acid. Epoxide 15 is obtained from trans -cinnamyl alcohol ( 14 ) and m -chloroperoxybenzoic acid ( m CPBA) in excellent yield (Scheme ).…”

“…The ring-opening reaction of epoxide 15 with 2-(methoxymethoxy)­phenol in the presence of sodium hydroxide affords 39 . Protection of the 1° alcohol unit of 39 is attained selectively with nitrobenzoyl chloride, affording compound 40 . Treatment of precursor 40 with mesyl chloride (MsCl) in the presence of Et 3 N yields ester 41 in almost quantitative yield.…”

“…The reaction of 41 with sodium hydroxide delivers 42 , and the ring-opening reaction of oxirane 42 is achieved with aqueous NH 3 to provide 43 (Scheme ). 44 is obtained by treatment of 43 with chloroacetyl chloride in the presence of Et 3 N followed by treatment with t -BuOH and t -BuOK to give amide 44 in 64% yield over two steps. The reduction of amide 44 is accomplished with Red-Al in toluene to deliver 45 .…”

“…However, the key feature of this synthesis is that this protocol allows the synthesis of ( S , S )-reboxetine as well as its analogues. By applying this approach, one can synthesize different analogues of ( S , S )-reboxetine …”