Boehringer Ingelheim synthesis

Bio-Mega/Boehringer Ingelheim have used an oxazolidinone auxiliary in the synthesis of renin inhibitors (e.g., 40) for the treatment of hypertension and congestive heart failure.58 A multi-step derivitization of the oxazolidinone 41 from reaction of (6)-4-(l-methylethyl)-2-oxazolidinone and 4-bromo-4-pentenoic acid yielded the desired compound. 

Boehringer Ingelheim applied a chiral auxiliary for introduction of the trifluor-omethyl group in their synthesis of indole and azaindole trifluoropentanols (Figure 9.7). Under tetrabutylammonium fluoride catalysis the trifluoromethylation to the chiral a-ketocarboxylate ester results in a 84 16 diastereoselectivity. Further crystallization yields enantiopure material that is saponified to the acid under recovery of the chiral auxiliary. Transformation to the epoxide and construction of the azaindole from alkynyl pyridine [73] give access to the whole class of enantiopure pentanol indoles and azaindoles including BI 115. 

In particular, the non-naturally occurring amino acid L-tert-leucine has received significant attention due to several pharmaceutically active compounds into which it is incorporated[1). HIV-protease inhibitors developed by Novartis and Abbott are based on L-tert-leudne 2, 3. Roche has developed the anti-arthritic compound Ro 31-9790 based on its potent inhibition of collagenase 41 and a key component in the synthesis of Ro 31-9790 is the methylamide of L-tert-leucine. Boehringer Ingelheim developed a series of compounds that inhibit the ribonucleotide redudase of Herpes... 

Two other research groups, Ward et al. (Boehringer Ingelheim Pharmaceuticals) and Willoughby et al. (Merck Research Laboratories) succeded in expanding the amination protocol to the solid phase synthesis of aryl amines. [12] Thus, this new reaction was already added to the tools of combinatorial synthesis. 

The first-developed method for the enantioselective construction of secondary aminated stereocenters, by Knowles, was the hydrogenation of enamides such as 11. In the context of a synthesis of BILN 2061 15, an antiviral protease inhibitor, Anne-Maiie Faucher of Boehringer-Ingelheim, Laval has shown (Organic Lett. 2004, 6, 2901) that such hydrogenations can be effected even in the presence of a terminal vinyl group. The product 12 was carried on to 15 over several steps, including the Ru (Hoyveda) cyclization of 13 to 14. 

Isoprenahne was developed by Boehringer Ingelheim, and a patent was applied for in 1939. [120] The synthesis starts from 2-chloro-3 4 -dihydroxyacetophe-none, which is reacted with isopropylamine. Then the keto-group is hydrogenated in presence of a palladium catalyst. Resolution of the racemate into its enantiomers is achievable with (+)-tartaric acid. Irrespectively, the commercial product is the racemate. 

Clenbuterol is a product from Boehringer Ingelheim. [123] There are several syntheses reported for this product, which were in part developed by Thomae as well. The starting material for the first synthesis presented here is 4 -nitroace-tophenone. The amine is again introduced in analogy to the previous syntheses. The target compound is obtained by chlorination of the aromatic ring and reduction of the ketone with sodium borohydride. 

For a recent application of 6a in synthesis of hepatitis C antiviral agent, BILN 2061, see WO 2004/089974 Al, Boehringer Ingelheim International GmbH, 2004. 

Boehringer Ingelheim (Germany)— isolation from ergot Galena (Czech Rep.)— isolation from ergot Lek (Slovenia)—fermentation Novartis (Switzerland)—synthesis Poli (Italy)—fermentation Manufacture 1. Isolation from field ergot... 

The trifluoromethyl epoxide 150 is an important intermediate in the synthesis of the anti-inflammatory drug lead BI-115 (17, Scheme 2.24). Researchers at Boehringer Ingelheim developed an efficient protocol for the synthesis of the a-trifluoromethyl-a-alkyl epoxide 150 that involved use of (lR,2S)-trans-2-phenylcy-clohexanol 146 as a chiral auxiliary for the asymmetric addition of a trifluoromethyl anion to the a-keto ester 147 153 synthesis of 150 initiated with the esterification of the a-keto acid 145 with (lR,2S)-trans-2-... 

Song JJ, Tan Z, Yee NK, Senanayake CH, Xu J, Gallou, inventors Boehringer Ingelheim Corporation, assignee. Stereoselective synthesis of certain trifluoromethyl-substituted alcohols. US Patent 0209488 Al. 2005 Sep 22. 

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