RR-amine process

The above RR-amine process, based on RR-amine (VI), was used for the first approximately two-year production program supplying most of the early requirements of bulk drug for the Clinical, Toxicology, and Pharmaceutical Development... 

Initially, only a small effort was disposed to assess the feasibility of the simpler synthesis. This grew at the expense of the RR-amine process because it became evident that this process was, like its forerunner (the separation of labetalol isomers), unlikely to achieve the Marketing COG target. Ideas for radically different syntheses were given an even lower priority and were often left to bootleg efforts by the originators. 

The simpler synthesis was built on the same premise as the RR-amine process , namely that it should be based on the existing labetalol process, particularly in terms of using the same or similar raw materials and intermediates, wherever possible, and also using similar plant equipment. The simpler synthesis grew out of a critique of the disadvantages of the RR-amine process (Scheme 4). 

The product of the simpler synthesis was compared in detail with the product of the RR-amine process. In particular, the Research Quality Control Unit searched for the presence of different polymorphs and new impurities (e.g., the dialkylation byproduct from the first step). They compared the stabilities of both products and also compared the hardness and dissolution rates of tablets made from both products. Since the DBTA resolution, crystallization, and product isolation steps, as wll as the final dilevalol hydrochloride preparation step, were the same for both the RR-amine process and the simpler synthesis, it was anticipated that these steps should protect against the introduction of new impurities or changed physical parameters in the final crystalline product. Such proved to be the case. 

FDA Review and Compliance Activities. A package of information detailing the above simpler synthesis and the definitive work carried out in Chemical Development, Research QC and Pharmaceutical Development to show equivalence versus the original RR-amine process was approved by the Review Branch of the FDA s Cardiovascular Division at a meeting in Rockville. This package provided the basis for the NDA filing. 

The asymmetric synthesis of indolizidine alkaloids is described utilizing a palladium-catalyzed amination process. Ionization of an allylic carbonate provides a symmetrical rr-allyl palladium complex, subsequent reaction with a protected homoallylamine gave the product in 93% yield and >99.5% ee (eq 5). ... 

Inorganic bases have been also employed in this system. When Butcher first used alkali carbonates [50], it was reported that, in DMF and at ambient temperature, the carbamation of primary and secondary aliphatic amines (or also arylamines) with alkyl halides under a C02 atmosphere (0.1 MPa) was effectively promoted by Cs2C03 [50, 51]. The Cs+ cations in the solvent used (DMF) did not form ion pairs with counterions, and favored the formation of naked carbamate anions that were more reactive at the O-ends with alkyl halides. Jung further found that the addition of tetrabutylammonium iodide (TBAI) to the system RR NH/ C02/RX/Cs2C03/DMF promoted the carbamation process with a higher yield and selectivity with respect to N-alkylation [51]. The process has been successfully extended to the synthesis of carbamate functionalities on solid phases. In this case, resin-bound carbamates are readily released from the resin by treatment with LiAlH4 in THF, yielding the respective N-methyl secondary amines [51]. 

In this approach the R-amine moiety in in was considered likely, in view of the work of Yamada and Koga5 and later Kametani et al.,6 to provide some inductive control in the sodium borohydride reduction of IV. Moreover, the R-amine moiety is a necessary component of dilevalol. Desired inductive control was quickly demonstrated by Gold et al. (internal communication, October 25,1979). However, a broad study of process conditions, particularly of solvent and temperature effects, only gave, at best, a ratio of RR to SR of... 

For assaying the enantiomeric purity of dilevalol in the DBTA salt, the Schering Research Analytical Department worked out an efficient glc procedure, utilizing methylboronic acid. Although the method did not separate RR and SS enantiomers or RS and SR enantiomers, it served to quickly indicate the efficiency of the resolution process since no racemization of the R-amine moiety was ever found. A typical glc trace was as follows ... 

Alcohols (as well as amines, sulfides and many hydrocarbons) may act as overall hydride donors towards excited nonbonding-rr " states of carbonyl compounds and heterocycles. The synthetic as well as the photophysical aspects of these processes have been discussed extensively. These reactions will not be dealt with further here. Singlet oxygen also accepts hydride from alkoxides in the gas phase the mechanisms of such reactions have received considerable study. ... 

Silverman and Zieske have rationalized how a protein nucleophile other than flavin is involved in MAO inactivation reactions, and why different inactivator compounds specifically react with flavin, protein amino acids, or both (100). Hydrogen atom donation from a cysteine residue to the flavin semiquinone radical would produce a thiyl radical, which could then capture the primary or secondary alkyl radical generated on cyclopropyl ring opening from the amine radical cation of the inactivator. The hydrogen atom abstraction reaction between the flavin and active site amino acid may be an equilibrium process such that either species could be present at any turnover. Hence, a combination of steric constraints and proximity to either the flavin semiquinone radical or the thiol radical will determine the site of adduct formation for a particular inactivator structure. A two-dimensional representation is shown in Scheme 23 (compounds 40-42), which illustrates the proposed equilibrium between the flavin semiquinone radical and amino acid as well as the proposed intermediates for the inactivation of MAO by A-(l-methylcyclopropyl)benzylamine 40 (104), rrradical center relative to the particular protein radical is consistent with proposed site of attachment of inactivator to protein 40 is near the flavin radical, such that exclusive flavin attachment occurs, 41 is positioned closer to the amino... 

The phrase conducted tour mechanism was coined by Cram to describe the removal of a proton by a base and its subsequent return to a different face of the same molecule from which it was removed [Ij. Originally, the conducted tour mechanism was postulated to explain the observation that rates of racemization of deuterated carbon acids were faster than hydrogen-deuterium exchange in solutions of potassium r rr-butoxide/rerf-butyl alcohol. Thus, the basic catalyst takes hydrogen or deuterium on a conducted tour of the substrate from one face of the molecule to the [other] (ref. [1], p. 101). This process was envisioned as a rotation of the carbanion within the solvent cage. We now recognize that the secondary amine forms a mixed aggregate with the enolate, such that the reprotonation (and perhaps conformational motion) is intrasupramolecular. ... 

Quinoid compounds are excellent acceptors of electrons and form electron donor-acceptor (EDA) complexes as a consequence of low-lying unoccupied electronic energy levels205. The EDA complexes may be easily formed in interactions with phenolic or amine components of a stabilizing mixture, with other additives which have reactive H atoms, with RO 2 radicals, or with some metallic impurities in polymers via rr-orbital interactions. Quinones efficiently participate in oxidation of polymers by virtue of these processes. 

The direct, Pd(II)-catalyzed addition of heteroatom and stabilized carbon nucleophiles to alkenes is generally not a successful reaction. An exception is the addition of water, which gives carbonyl compounds and has been developed into an important indnstrial process, the Wacker process. This has been reviewed extensively.By contrast, the stoichiometric addition of nucleophiles such as amines is facile. - However, if alkenes could be converted catalytically into Tr-allylpalladium complexes, the problems with nucleophilic addition to alkenes could be circumvented and amines and other heteroatom nucleophiles could be employed. A range of alkenes have been converted into rr-allyl complexes in a stoichiometric fashion,t "t but catalytic reactions have proved more difficult. However, aUyl acetates and similar compounds readily exchange the acetate group for heteroatom nucleophiles in a Pd(0)-catalyzed reaction, which proceeds via 7T-allylpalladinm(ll) intermediates (Scheme 1). Since this reaction has been developed into a very important synthetic reaction, an efficient procedure for catalytic conversion of alkenes into aUyl acetates would have great synthetic potential. 

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