Large-Scale Synthesis of the Glucosylceramide Synthase Inhibitor N-[5-(Adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin

Abstract

A synthetic route for the preparation of glucosylceramide synthase inhibitor N-[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin methanesulfonic acid salt (AMP-DNM) has been developed. Herein we report the development and optimization of this synthetic route from its initial version in an academic research laboratory at milligram-scale to the final optimized route that was implemented in a cGMP miniplant on kilogram-scale. The definitive route starts with the separate synthesis of building blocks 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin and 5-(adamantan-1-yl-methoxy)-pentanal. The aldehyde was synthesized from 1,5-pentanediol in five steps and 45% overall yield. Protected 1-deoxynojirimycin was prepared by a successive hemiacetal reduction/Swern oxidation/double reductive amination sequence of 2,3,4,5-tetra-O-benzyl-d-glucopyranose in 52% overall yield. Reductive amination of the two building blocks produced the benzyl-protected penultimate that was isolated as its crystalline (+)DTTA salt in 68% yield. Hydrogenolysis of the penultimate and crystallization of the end product as its methanesulfonic acid salt produced AMP-DNM in 76% yield with a purity of >99.5%. The described route enables the production of multikilogram amounts of inhibitor AMP-DNM as a stable crystalline solid with high purity under cGMP control.

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

“…The preparation of the iminosugar library follows wellestablished routes of synthesis previously reported by us 35,39 and others. 40,41 Details on the preparation and characterization of all compounds are provided in the Supporting Information.…”

Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2

“…Following that, the benzyl protecting groups of the N ‐butyl‐aminocyclopentitols 34 were removed under hydrogenolysis conditions to yield 35 a and 35 c , while Birch conditions were needed to obtain the N ‐nonyl derivatives 35 b and 35 d . For the synthesis of compound 35 f , amino alcohol 33 was subjected to hydrogenolysis to furnish intermediate aminotriol 35 e , which was then reacted with 5‐(adamantan‐1‐yl)methoxy)pentanal following a reported procedure and subjected to reductive amination to generate the targeted adamantyl 35 f .…”

“…Better yields and only mono-alkylated products were obtained when the HCl salt of 33 (Et 3 Nw as used to neutralize the reaction medium) was used, providing improved yields (49!73 % and 41!70 %, respectively) of 34 a and 34 b.S ubsequently, compounds 34 c-34 d were prepared using the same protocol. Following that, the benzyl protecting groups of the N-butylaminocyclopentitols 34 were removed under hydrogenolysis conditions to yield 35 a and 35 c,w hile Birch conditions were neededt oo btain the N-nonyl derivatives 35 b and 35 d.F or the synthesis of compound 35 f,amino alcohol 33 was subjected to hydrogenolysis to furnish intermediate aminotriol 35 e, which was then reactedw ith 5-(adamantan-1-yl)methoxy)pentanal following ar eported procedure [46] and subjected to reductive amination to generate the targeted adamantyl 35 f.…”

Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors

“…Each of these 13 cyclic secondary amines was connected to thec ore aminodiol that is the common feature in all compounds, and further variation was providedb yi ntroducing three different N-acyl groups:n ext to the adamantane spacer (taken from lead 2), the nonanoic acid moiety as present in lead 3,a nd O-(p-methoxypenyl)hydroxyacetate as another hydrophobic moiety found in GCS inhibitors of the PDMP series. [12] In all, this led to the following 13 series of three compounds each:p olyhydroxylated piperidines featuring the d-gluco configuration( 11-13), the l-ido configuration( 14-16), the d-galacto configuration (17-19)a nd the l-altro configuration (20)(21)(22); polyhydroxylated pyrrolidines featuring the d-lyxo configuration (23)(24)(25), the d-arabino configuration (26)(27)(28), the d-xylo configuration (29)(30)(31), the d-ribo configuration (32-34), the l-arabino configuration (35-37)a nd the l-lyxo configuration (38-40); along with the analogous compounds featuring an unsubstituted piperidine (41-43), morpholine (44-46), and pyrrolidine (3,47,48).…”