BASF process acylation

Another important difference between (dynamic) kinetic resolution of alcohols and amines is the ease with which the acylated product, an ester and an amide, respectively, is hydrolyzed. This is necessary in order to recover the substrate enantiomer which has undergone acylation. Ester hydrolysis is generally a facile process but amide hydrolysis, in contrast, is often not trivial. For example, in the BASF process [28] for amine resolution by lipase-catalyzed acylation the amide product is hydrolyzed using NaOH in aq. ethylene glycol at 150 °C (Fig. 9.18). In the case of phenethylamine this does not present a problem but it will obviously lead to problems with a variety of amines containing other functional groups. 

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. 

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. 

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-... 

Processes for the synthesis of metrafenone have been described in two BASF patents [19, 20]. The benzophenone can be obtained by an iron(iii) chloride catalyzed Friedel-Crafts acylation of 3,4,5-trimethoxytoluene. The appropriate benzoyl chloride is easily accessible by bromination of 2-methoxy-6-methylbenzoic acid and subsequent conversion into the acid chloride. (Scheme 22.2)... 

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