Drug synthesis epoxidation

Senanayake, C. H., Jacobsen, E. N. Chiral (Salen)Mn(III) Complexes in Asymmetric Epoxidations Practical Synthesis of Ci s - Am i n o i n d ano 1 and Its Application to Enantiopure Drug Synthesis, Process Chemistry in the Pharmaceutical Industry, Gadamasetti, K. G. Marcel Dekker New York, 1999, Chapter 18, 327. 

The seminal enantioselective allylic alcohols epoxidation realized by Katsuki and Sharpless [18] to which other similarly steroselective reactions soon followed (e.g., bishydroxyla-tion, cyclopropanation, lactonization and catalytic hydrogenation) have been invaluable for this purpose. One of the most significant applications, as far as drug synthesis is concerned, of the Sharpless method from the innumerable ones which have been found in the past 20 years is the routine preparation (Fig. 6) of antipodal pairs of known chirality of (3-blockers such as propranolol (5) [19]. 

The second system studied was the separation of the chiral epoxide enantiomers (la,2,7,7a-tetrahydro-3-methoxynaphth-(2,3b)-oxirane Sandoz Pharma) used as an intermediate in the enantioselective synthesis of optically active drugs. The SMB has been used to carry out this chiral separation [27, 34, 35]. The separation can be performed using microcrystalline cellulose triacetate as stationary phase with an average particle diameter greater than 45 )tm. The eluent used was pure methanol. A... 

Scheme 4.10 gives some examples of application of alkyne carboalumination in synthesis. The reaction in Entry 1 was carried out as part of a synthesis of the immunosuppressant drug FK-506. The vinyl alane was subsequently transmetallated to a cuprate reagent (see Chapter 8). In Entry 2, the vinyl alane was used as a nucleophile for opening an epoxide ring and extending the carbon chain by two atoms. In Entries 3 to 5, the vinyl alane adducts were converted to vinyl iodides. In Entry 6, the vinyl alane was converted to an ate reagent prior to reaction with formaldehyde. 

The enantioseiective hydrogenation of a-amino ketones has been applied extensively to the synthesis of chiral drugs such as the / -agonist SR 58611 (Sanofi Cie). m-Chlorstyreneoxide was obtained via carbene-induced ring closure of the amino alcohol. Epoxide-opening by a chiral amine obtained via a ruthenium-catalyzed hydrogenation of an enamide has led to the desired compound where... 

The asymmetric hydrogenation of cinnamic acid derivatives has been developed by Knowles at Monsanto [4], The synthesis of L-dopa (Figure 4.3), a drug for the treatment of Parkinson s disease, has been developed and is applied on an industrial scale. Knowles received the Nobel Prize for Chemistry in 2001 together with Noyori (see below, BINAP ) and Sharpless (asymmetric epoxidation). 

In addition, new some epoxide hydrolases have also shown a great utility for the desymmetrization of meso-epoxides. An interesting example is the synthesis of nelfinavir-the active pharmaceutical ingredient (API) of the anti-human immunodeficiency virus drug Viracept-where the (R,R)-diol obtained by opening the meso-epoxide is a suitable starting material. Scheme 10.6 shows a synthetic route to nehinavir [14]. 

At least two systems can be cited as catalysts of peroxide oxidation the first are the iron (III) porphyrins (44) and the second are the Gif reagents (45,46), based on iron salt catalysis in a pyridine/acetic acid solvent with peroxide reagents and other oxidants. The author s opinion is that more than systems for stress testing these are tools useful for the synthesis of impurities, especially epoxides. From another point of view, they are often considered as potential biomimetic systems, predicting drug metabolism. Metabolites are sometimes also degradation impurities, but this is not a general rule, because enzymes and free radicals have different reactivity an example is the metabolic synthesis of arene oxides that never can be obtained by radical oxidation. 

In a comparison study for the synthesis of the arrhythmia and hypertension drug candidate 7, the intermediate epoxide 8 was prepared by a Sharpless dihydroxylation and a Jacobsen HKR. The latter HKR method gave the highest ee s.116... 

Triazoles and tetrazoles can be alkylated on nitrogen under basic conditions, as in the synthesis of the clinically-used antifungal drug 8.35 in which 11,2,4-triazole is alkylated by a chloromethyl ketone and an epoxide, both good alkylating agents. What is the mechanism of formation of epoxide 8.34 Of compounds 8.34 and 8.35, which is achiral and which is racemic ... 

Batch reactors based on peroxidases are mainly applied for degradation purposes (see Chap. 8). LiP, manganese peroxidase (MnP), HRP, SBP, and CPO were used for the oxidation of phenolic compounds [3, 6, 7, 9, 20, 38, 74, 75, 95], decoloriza-tion of dye-containing effluents [5, 22], and pulp biobleaching [59]. In the field of synthesis, CPO is the most versatile and promising of the peroxidases (see Chap. 6). It was applied in discontinuous operation for epoxidations [78,79], enantioselective oxidations of alcohols to aldehydes [14,48], halogenations [77,80], hydroxylations, and oxidation of indole to oxindole, which is an important drug precursor [96]. 

The body oxidizes the alkene components of drugs and other substances to epoxides, which are then hydrolyzed to diols by an epoxide hydrolase enzyme. The more reactive epoxides are rapidly converted to water-soluble diols and eliminated in the urine. Epoxide hydrolase enzymes are sometimes used in organic synthesis to produce chiral diols. 

Moxnidazole is,an antiparasitic drug, and our next target molecule is an important intermediate in its synthesis, The obvious first disconnection is of the carbamate group, revealing two 1,2 relationships. A 1,2-diX disconnection gives an epoxide that can be made by alkylation of morpholine with epiehlorohydrin,... 

The simplest route to certain potential (3-blocker drugs is from an epoxide, and the chemists working on their synthesis decided that, since 4-cyclopropylbenzaldehyde was more readily available than 4-cyclopropyl styrene, they would use the aldehyde as the starting material and make the epoxide in one step using a sulfonium ylid. 

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