Practical Diastereoselective Synthesis and Scale-up Study of (+)-2-((1R,2R,3R,5S)-2-Amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol: A Key Intermediate of the Novel Prostaglandin D₂ Receptor Antagonist S-5751

Abstract

A new synthetic process was developed for (+)-2-((1R,2R,3R,5S)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol, a key intermediate of S-5751. Diastereoselective alkylation of (+)-nopinone with ethyl bromoacetate, formation of O-methyl oxime, and diastereoselective reduction with NaBH 4 -AlCl 3 could be safely carried out. Stereochemistry of the (1R,2R,3R,5S)-6,6-dimethylbicyclo[3.1.1]heptane ring was discussed to achieve high diastereoselectivity on these reactions. For the scale-up, detailed consideration was given to the safety of the NaBH 4 -AlCl 3 reduction.

Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

“…In the Genzyme route, amide reduction was conducted using LiAlH 4 , which also worked well with amide 4 in our case (Table 4, entry 1). However, considering the safety issue related to LiAlH 4 for pilot-scale manufacturing, 15 alternative reagents were investigated (Table 4, entries 2−8). Early work showed that NaBH 4 /TFA gave low conversion in amide reduction (Table 4, entry 2).…”

Reduction of liquid terminated-carboxyl fluoroelastomers using NaBH4/SmCl3

“…Nonetheless, NaBH 4 does not directly reduce the carboxylic acids by reason of its relatively weak reductive activity. To reduce carboxylic acid compounds effectively, many Lewis acids have been developed to improve the reduction activity of NaBH 4 including I 2 , 21 ZnCl 2 , 22 LiCl, 23 AlCl 3 , 24 CoCl 2 (ref. 25) and so on.…”

Stabilization of NaBH4 in Methanol Using a Catalytic Amount of NaOMe. Reduction of Esters and Lactones at Room Temperature without Solvent-Induced Loss of Hydride

“…Scheme summarizes the known methods for the reduction of esters with NaBH 4 in methanol. Addition of metal salts, such as LiCl, LiBr, MgCl 2 , CaCl 2 , ZnCl 2 , and AlCl 3 , to sodium borohydride increases its reduction capabilities (Scheme , entry 1). − There are also reports of the reduction of esters using NaBH 4 in the presence of Ce or Co catalyst (Scheme , entry 2) supported on cationic surfaces . Under reflux conditions, NaBH 4 has been reported to reduce esters in protic solvents (Scheme , entry 3). ,− Esters bearing substituents like hydroxyl/oxo/amino in the α- or β-positions have been reduced by NaBH 4 via intramolecular hydride transfer (Scheme , entry 4). − Unfortunately, alcohol solvents, such as methanol, are not compatible with NaBH 4 at elevated temperatures because decomposition of NaBH 4 becomes competitive with the reduction.…”