Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine

Lisa K Thalén,Jan-E Bäckvall

doi:10.3762/bjoc.6.97

Abstract

Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1-phenylethylamine (1). Several reaction parameters have been investigated to modify the method for application on multigram scale. A comparison of isopropyl acetate and alkyl methoxyacetates as acyl donors was carried out. It was found that lower catalyst loadings could be used to obtain (R)-2-methoxy-N-(1-phenylethyl)acetamide (3) in good yield and high ee when alkyl methoxyacetates were used as acyl donors compared to when isopropyl acetate was used as the acyl donor. The catalyst loading could be decreased to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 when alkyl methoxyacetates were used as the acyl donor.

Highlights

Chiral amines are important building blocks in the synthesis of many pharmaceuticals, fragrances, and agricultural products, and it is important to develop methods for their preparation that are applicable on multigram scale
We have previously developed a highly efficient protocol for the dynamic kinetic resolution (DKR) of primary amines using Candida antarctica lipase B (CALB) as the enzyme and 4 as the racemization catalyst
A comparison of isopropyl acetate and alkyl methoxyacetates as the acyl donor was carried out

Summary

Introduction

Chiral amines are important building blocks in the synthesis of many pharmaceuticals, fragrances, and agricultural products, and it is important to develop methods for their preparation that are applicable on multigram scale. The previously reported conditions for application of DKR to 1 (Scheme 1) were as follows: 4 mol % racemization catalyst 4, 20 mg CALB, 6.8 equivalents isopropyl acetate (5) (Figure 1), and 20 mg sodium carbonate in 8 mL of toluene at 90 °C (Table 1, entry 1). It was found that a marked decrease in the reaction rate was observed when the excess of acyl donor 5 was decreased from 6.8 equiv to 1.5 equiv (Table 1, entries 1–3).

Results

Conclusion