Chiral amines BASF process

Scheme 7.10 The resolution of chiral amines examples of the substrate range used by the BASF process demonstrated on a multi-ton scale.

Enzyme-based processes for the resolution of chiral amines have been widely reported [2, 3] and are used in the manufacture of pharmaceuticals, for example, BASF s process for chiral benzylic amine intermediates. Scheme 13.1 [4]. The methods used are enantioselective hydrolysis of an amide and enantioselective synthesis of an amide, both of which are kinetic resolutions. For high optical purity products the processes depend upon a large difference in the catalyzed reaction rates of each enantiomer. 

Hundreds of impressive examples of enantioselective lipase-catalysed reactions are known, including industrial processes as in the case of the BASF method of chiral amine production (Collins et al. 1997 Breuer et al. 2004 Schmid and Verger 1998). However, the classical problem of substrate acceptance or lack of enantioselectivity (or both) persists. We were able to meet this challenge in model studies regarding the hydrolytic kinetic resolution of the ester rac-1 with formation of carboxylic acid 2, catalysed by the lipase from Pseudomonas aeruginosa. The wild-type (WT) lipase is only slightly (S )-selective, the selectivity factor amounting to a mere E = 1.1 (Scheme 1). 

Several multi-ton industrial processes still use enzymatic resolution, often with lipases that tolerate different substrates. BASF, for example, makes a range of chiral amines by acylating racemic amines with proprietary esters. Only one enantiomer is acylated to an amide, which can be readily separated from the unreacted amine. Many fine chemicals producers also employ acylases and amidases to resolve chiral amino acids on a large scale. l-Acylases, for example, can resolve acyl d,l-amino acids by producing the I-amino acids and leaving the N-acyl-l-amino acid untouched after separation, the latter can be racemized and returned to the reaction. d-Acylase forms the alternative product. Likewise, DSM and others have an amidase process that works on the same principle d,l-amino acid amides are selectively hydrolyzed, and the remaining d-amino acid amide can be either racemized or chemically hydrolyzed. 

Figure 14.11 BASF process for the synthesis of a wide range of chiral amines.

Optically active amines are important intermediates and chiral auxiliaries in the technical synthesis of agrochemicals and pharmaceuticals. BASF, one of the world s leading producers of chiral amines, developed a process based on the enzymatic resolution of racemic amines 49 with Burkholderia plantarii lipase immobilized on polyacrylate (Scheme 16) [75,76]. Methoxyacetic acid estars are particularly well suited for the stereospecific enzymatic differentiation, giving both the free amine (S)-49 and the acylated product R)-50 in high ee. The reaction stops at 50% conversion and the selectivity factor was calculated to be as high as 500. A plug-flow or batch reactor can be used for the enzymatic reaction and the residence time is in the range of 5-7 h. The more important amine (R)-49 can be liberated with the aid of base and is subsequently purified by distil-... 

BASF successfully developed a process, which is operated on a rnulti-thousand-ton scale, for the resolution of chiral primary amines by lipase-catalyzed acylation... 

Biocatalytic resolution has been applied efficiently by BASF for the manufacture of optically active amines, such as phenylethylamine [96]. The process is based on a highly stereoselective resolution of racemic amines by means of an acylation reaction in the presence of a lipase as a catalyst (Scheme 22). The products are obtained in high yields and with excellent enantioselectivities. The unrequited enantiomer can be racemized subsequently. Thus, starting from a racemate, efficient access (with theoretically 100% yield) to the (/ )- and (5)-amine, respectively, is available. This technology, which is said to be carried out on a > 1000 mt scale, has been extended recently by BASF to the production of chiral alcohols. 

Normally, when a chiral compound is synthesized by conventional chemical means, a racanic mixture of the two enantiomers is produced. Because of their essentially identical chemical properties, they are very hard to separate. However, it is possible to produce enantiomerically pure chemical compounds with appropriate enzymatic catalysts. Furthermore, it is possible to use enzymatic catalysts to convert racemic mixtures of compounds to enantiomerically pure forms. In one of the larger such industrial operations, the German chmical firm BASF now uses enzymatically catalyzed processes to prepare enantiomerically pure amines in thousand-ton quantities. 

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