Bristol-Myers Squibb synthesis

SCHEME 2.6. Bristol-Myers Squibb synthesis of peliglitazar 39. 

A simple and atom-economical synthesis of hydrogen halide salts of primary amines directly from the corresponding halides, which avoids the production of significant amounts of secondary amine side products, has been described by researchers from Bristol-Myers Squibb [227]. Microwave irradiation of a variety of alkyl halides or tosylates in a commercially available 7 m solution of ammonia in methanol at 100-130 °C for 15 min to 2.5 h followed by evaporation of the solvent provided the corre-... 

As an example, we present in Exhibit 10.8 the synthesis of paditaxel (Taxol, Bristol-Myers Squibb), an important anticancer drug for breast and ovarian cancer and Kaposi sarcoma. It illustrates the complexity in the synthesis of drug molecules. 

A conceptually similar approach applied in an industrial process is described by the Bristol—Myers—Squibb group, who required l-6-OH norleucine as an intermediate in the synthesis of their drug Omapatrilat. T o avoid a lengthy chemical synthesis of the oxoacid, it was more convenient to start with the racemic amino acid, readily prepared by hydrolysis of the corresponding hydantoin (Equation (2)), and remove the D-isomer by oxidation using d-AAO. 

There are five basic sources of pharmaceuticals. By dollar value of products, fermentation is probably the most important, whereas by tonnage, chemical synthesis is dominant. Fermentation is used for antibiotics such as penicillins and tetracyclines. Chemical synthesis provides drugs such as the psychotropics and antihistamines. Animal extracts provide hormones. Biological sources lead to vaccines and serums. Vegetable extracts provide steroids and alkaloids. The top ten pharmaceutical companies in order of revenues are the following Merck, Pfizer, Bristol-Myers Squibb, Johnson ... 

The successful execution of this study was enabled by the NSF through CHE-0071887 and a predoctoral fellowship to M. J. E. The Center for New Directions in Organic Synthesis is supported by Bristol-Myers-Squibb as a Sponsoring Member and Novartis as a Supporting Member. Finally, M. J. E. benefited greatly from the presence of Maya Ponte. 

To better appreciate the standard by which inequitable conduct is measured, let s review an actual recent court opinion, Bristol-Myers Squibb Company v. Rhone-Poulenc Rorer, Inc.,1% where this issue was heard. This case serves to explain how materiality and intent are inextricably related. Perhaps less abstractly, it will also show why it is important for the scientists to pay close attention to what they publish as well as to documents that they are asked to review.79 This decision arose from an appeal from theU.S. District Court for the Southern District of New York (D-SDNY), which held the Rhone-Poulenc Rorer (RPR) patent relating to methods of preparing Taxol (hereinafter referred to by its generic name paclitaxel) as well as claiming key intermediates in the paclitaxel synthesis to be unenforceable due to inequitable conduct. A brief review of the facts of the case is presented next. 

Scientists at Bristol-Myers Squibb, after screening various microorganisms, selected a bacterial strain of Acinetobacter calcoaceticus SC 13876 to reduce a 3,5-dioxo ester 20 to the dihydroxy ester 21 (Scheme 19.13).103 The diol 21 is a key intermediate in the synthesis of an HMG-CoA reductase inhibitor (22). In a 1-L batch reaction, a yield of 92% was obtained with an optical purity... 

In another study, screening was carried out for reduction of substituted benzazepin-2,3-dione 23 to a 3-hydroxy derivative 24 (Scheme 19.14). This was accomplished by a bacterial strain of Rhodococcus fascians ATCC 12975 (Norcardia salmonicolor SC 6310) with a conversion of 97% and an optical purity of >99.9%. This reaction product 24 is a key intermediate in the synthesis of the calcium antagonist SQ 31,765 (25).104 105 The Bristol-Myers Squibb group has also shown the selective reduction of the (3-keto ester, methyl-4-chloro-3-oxobutanoate, by the fungus Geotrichum candidum SC 5469 to the corresponding (,S )-hydroxy ester.106... 

A transaminase patented by Celgene Corporation (Warren, NJ), called an co-aminotransferase [(co-AT)E.C. 2.6.1.18] does not require an a-amino acid as amino donor instead it requires a primary amine and hence has the ability to produce chiral amines.125 126 A similar co-AT from Vibrio fluvialis has been described for the production of chiral amines along with chiral alcohols when coupled with AdH or chiral amino acids when coupled with an a-amino acid aminotransferase.127130 Another co-AT, ornithine (lysine) aminotransferase (E.C. 2.6.1.68), has been described for the preparation of a chiral pharmaceutical intermediate used in the synthesis of Omapatrilat, a vasopep-tidase inhibitor developed by Bristol-Myers Squibb, as well as the UAA A1 -piperidinc-6-carboxylic acid.131-132... 

Another example using a prochiral acetate and asymmetric hydrolysis was described by the Bristol-Myers Squibb group for an intermediate in the synthesis of Monopril (fosinopril sodium) (41), an ACE inhibitor (Scheme 19.23). The prochiral substrate 42 was hydrolyzed both when R = phenyl or cyclohexyl to the corresponding (S)-(-)-monoacetate 43. The reaction was carried out in a 10% toluene biphasic system with either PPL or Chromobacterium viscosum lipase. The cyclohexyl monoacetate was obtained in 90% yield with an optical purity of 99.8%.107 195... 

Integration of automated amide synthesis with automated purification has been implemented by workers at Bristol-Myers Squibb [89] using a Zymark robotic system. 

The synthesis of the Bristol-Myers Squibb anti-migraine drug Avitriptan (a 5-HT1D receptor antagonist) involves this palladium-catalysed indole synthesis. Suggest a mechanism and comment on the regioselectivity of the alkyne attachment. 

Bristol-Myers Squibb in partnership with Otsuka has recently marketed aripiprazole for the treatment of schizophrenia. The synthesis (Scheme 20) begins with acylation of 3-methoxyaniline followed by Friedel-Crafts ring closure to give quinolinone 67. Hydrogenation provides dihydroquinolinone 68, which is treated with 1,4-dibromobutane in the presence of K2CO3 to afford 69. Compound 69 was treated with Nal and then alkylated with 2,3-dichlorophenylpiperazine to give aripiprazole (5). 

An example of the use of a symmetrical disulfide as a protecting group can be seen in a synthesis of compound 30.4 [Scheme 5.30], a key intermediate in Bristol-Myers Squibb s Omapatrilat.60 The tethered dipeptide derivative 30.2 of homocysteine was cleaved with dithiothreitol and the thiol intermediate treated with methanesulfonic acid to cause a double cyclisation reaction. 

---