ISIS-Chemie

According to Knowles [28], Monsanto has been producing L-dopa, a drug to relieve Parkinson s disease, on the scale of ca. 1 ty-1 for many years. A few years after Monsanto, the East-German company VEB Isis-Chemie also carried out this process on a similar scale but terminated the production after a few years [29]. The key step in the synthesis is the enantioselective hydrogenation of an enamide intermediate (Fig. 37.3). 

Homogeneous asymmetric hydrogenation is a practical synthetic method (27). The DIPAMP-Rh-catalyzed reaction has been used for the commercial production of (S)-DOPA [(5)-3-(3,4-dihydroxy-phenyl) alanine] used to treat Parkinson s disease (Monsanto Co. and VES Isis-Chemie) (Scheme 12) (27, 28). (S)-Phenylalanine, a component of the nonnutritive sweetener aspartame, is also prepared by en-antioselective hydrogenation (Anic S.p.A. and Enichem Synthesis) (29). A cationic PNNP-Rh(nbd) complex appears to be the best catalyst for this purpose (15c) (see Scheme 5 in Chapter 1). 

Rhodium catalysts that contain 10a have been reported for the industrial preparation of L-dopa (,cf Scheme 12.1). Similar to the Monsanto Rh(DIPAMP) process, the enamide 14a has been reduced with [Rh(COD)(10a)]+BF4 in >90% ee by VEB Isis-Chemie Zwickau.90... 

In January 1986 Isicom, a prescription drug used to treat the Parkinson syndrome, went on sale in the former German Democratic Republic. Isicom is a combination of L-dopa [L-dopa=(S)-3-(3,4-dihydroxyphenyl)-alanine] and L-carbidopa. For both components, new synthetic procedures were developed independently at the former Academy of Sciences of the GDR and the production of the active substances was realized at the former VEB ISIS-Chemie Zwickau. In this contribution the history and details of the development of the L-dopa process are recounted. For the commercial application of enantioselective catalysis, this is of some importance, since it was the first industrial process utilizing asymmetric complex catalysis to be realized in the former socialistic countries as well as in Europe. 

In 1978 we tried to establish contacts with an industrial partner, which were realized by talks with Dr. Lohmann, at that time head of the research department of the VEB ISIS-Chemie, Zwickau. Earlier it was a Kommanditgcscllschaff with government participation but was later converted into a nationalized state-run plant with the status of a VEB ( Volkseigener Betrieb , i.e., a firm owned by the people), a typical state-owned plant in the former GDR. The company was interested in producing L-dopa and we saw a good opportunity for an industrial process using the asymmetric hydrogenation of O-functionalized derivatives of (Z)-2-acetamidocinnamic acid 1 a with our catalysts as shown in Fig. 4. 

The process was introduced by the VEB ISIS-Chemie and the production of L-dopa began in 1985. Accounts of this were first published by its staff in 1987, having par-... 

An enlargement of the plant was envisioned because export into other socialistic countries was planned. However, production of L-dopa ended in 1990, one year after the collapse of the socialist system and one month after the management had actually decided to increase production capacity for L-dopa. The particular circumstances led to a general halt of all chemical manufacture by the successor companies of the former VEB ISIS-Chemie Zwickau ... 

I would like to express my deeply felt thanks to Prof. H. Pracejus for development of the field of asymmetric catalysis and to the staff of the research department of the former VEB ISIS-Chemie in Zwickau, particularly Dr. W. Vocke and Dr. F.-U. Flother, for the elaboration of the industrial L-dopa process. For practical assistance I particularly thank Mrs. R. Pinske, Mrs. H. Bumeleit, DC H. Foken, Dr. H. Griiner, Dr. R. Hanel and DC G. Konig. I gratefully acknowledge the support of Prof. G. Oehme, Dr. C. Fischer and Dr. H. Dreycr particularly with respect to analytical problems. I am indebted to Prof. H.-W. Krause for useful advice in many instances. 

In contrast to the Monsanto process, it was decided to use hippuric acid in the Erlenmeyer-Plochl condensation for the VEB ISIS-Chemie Zwickau procedure. 

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