Optimization Phase Development of an Economic Process

As even the optimized hydrogenation conditions gave rise to not more than 89% enantioselectivity it became very important to find an efficient purification procedure which would allow the enrichment of the desired (-(-enantiomer. A rapid screening of several weak and strong acids led to an acceptable solution. The acetates of both the racemate 11 as well as the (-)-enantiomer 12 are readily crystalline salts but the acetate of the desired (S)-enantiomer is less soluble in toluene at 0°C than that of the racemate by a factor of 10. Thus it could be crystallized in overall yield of 84%, content 99.1%, 98.9% ee. Finally it was noticed that traces of iridium (70-200 ppm) in the acetate salt hindered the following reaction in the synthetic sequence, by leading to decomposition of the formic acid (used as for-mylation reagent). A treatment of the octahydroisoquinoline solution with charcoal prior to precipitation of the acetate salt lowers the Ir content to 20-40 ppm. This new quality can then be formylated without problems under the standard conditions. 

A scale-up of the laboratory process into a 100 L BUSS type loop reactor at 70 bar was not trivial. Altogether 28 batches each of 5 kg 10 (as the phosphate salt) were hydrogenated. The first batches reacted considerably more slowly than expected, gave incomplete conversions, and high variations from batch to batch. Two major problems were identified  

Several changes to the initial conditions were tested in the laboratory and directly applied to the BUSS reactor 

The combination of these changes together with increasing the amount of catalyst then allowed us to attain complete conversion with good enantioselectivity and a TOF of 170 per hour. 

The finalized stable process conditions, S/C 1100, temperature 20 °C, pressure 70 bar, reaction time 6 hours, led to a conversion of 91.5-92.9% and a crude product with 80.4—81.4% ee, which could be crystallized as the acetate with a content of 99%, an ee of 98.1-98.4% and a yield of 75.2-76.5% based on 10. 

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