Resolutions at Large Scale Case Studies

An overwhelming majority of classic resolutions still involves the formation of diastereomeric salts of the racemate with a chiral acid or base (Table 1). These chiral resolving agents are relatively inexpensive and readily available in large quantities (Table 2). They also tend to form salts with good crystalline properties [6], 

Chiral acids or bases are tested for salt formation with tire target racemate in a variety of solvents. The selected diastereomeric salt must crystallize well, 

This new resolution process was equally efficient with greater than 95% theoretical yield, in addition to being much more cost effective due to the low cost of the resolving agent [10,11], 

Other asymmetric synthetic processes used for the manufacturing of (S)-(-l-)-naproxen can also be applied to the production of (S)-(-l-)-ibuprofen these include the Rh-phosphite catalyzed hydroformylation [33], hydrocyanation [21], and hydrocarboxylation reactions [20], 

Taking advantage of the ready availability of racemic ibuprofen, the resolution approach for production of (S)-(+)-ibuprofen becomes an attractive alternative. Merck s resolution process involves the formation of a diastereomeric salt of ibuprofen with (S)-lysine, an inexpensive and readily available natural amino acid [41], The racemic ibuprofen is mixed with 1.0 equivalent of (.S )-lysine in aqueous ethanol. The slurry is agitated to allow full dissolution. The supernatant. 

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This outline of the response theory has for simplicity been limited to molecules with axial symmetry of y and Aa and to the field on, field off cases, but can be extended in both respects without basic difficulties. Detailed comparisons with experiment have not yet been made, but it already is clear that Kerr effect relaxation data can now provide more valuable and better defined information about orientational dynamics of biopolymers and other molecules than was previously possible. With the increasing accuracy and time resolution of digital methods, it should be possible to study not only slow overall rotations of large molecules (microseconds or longer) but small conformational effects and small molecule reorientations on nano and picosecond time scales. Moreover, one can anticipate the possibilities, for simple problems at least, of extending response theory to other quadratic and higher order effects of strong electric fields on observable responses. 

When 1 was selected for scale-up, we were required to prepare very rapidly a moderate amount of material for initial studies (ca. SOOg) by i t is commonly referred to as an expedient synthesis.[4] Given the limited time firame and file pressure on the process chemist to deliver quickly an initial batch of the drug candidate, this route is usually file discovery route after suitable adjustments, fiiat is, in our specific case, the introduction of a resolution step. At the same time, we sought to develop a scalable route, i.e. one that could eventually deliver quickly and cheaply large amounts of material that will be required later on. 

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