Dilevalol

C7H()N 100-46-9) see Amosulalol Bamidipine Beclamide Benperidol Betanidine Biotin Cisapride Dilevalol Guanoxan Moxifloxacin hydrochloride NebivOlol Nialamide Reproterol Sparfloxacin Sulbentine Viloxazine benzylamine hydrochloride (C7H,()C1N 3287-99-8) see Benzyl mustard oil 2-benzylaminoethanol... 

Darodipine, 107 Dazoxiben, 91 Delapril, 58 Desciclovir, 165 Desipramine, 201 Desoximetasone, 70 Dezaguanine, 162,163 Dezocine, 59 Diazlquone, 51 Difloxacin, 143, 144, 145 Dilevalol, 20 Disoxarll, 86 Diuretic, 130,168 Domperidone, 133 Donetidine, 114 Dopamine, 20 Dopexamine, 22 Doxazosin, 148 Doxorubicin, 62 Dribendazole, 132 Duoperone, 199... 

To make his case, Kessler cited the example of a drug called Dilevalol, which he said was approved in Japan, Portugal, and England on the basis of data summaries. Americans, he said, were spared morbidity and mortality because the FDA medical reviewer noted in the raw data evidence that some patients had severe liver injury. Another untruth. The record shows it was... 

Undertaking manufacture of early launch bulk actives for Marketing was always controversial. It occurred in one case (see presentation on dilevalol hydrochloride) and, as it happened, the early launch manufacturing strategy saved enormously, by... 

The old process for the manufacture of albuterol5 requires the use of a number of chemicals, particularly formaldehyde and bromine, which are classified as extremely hazardous substances (and subject to reporting requirements under EPCRA and CAA—see later). Clearly, we preferred not to handle these. At the time, albuterol manufacture, because of its small volume, was being carried out in Chemical Development plants. Because we were enjoined to reduce wastes as part of our RCRA and EPCRA commitments, we initiated a search for a better and simpler process. Such a process evolved from our work on the manufacturing process for dilevalol hydrochloride (q.v.). Scheme 1 summarizes our first new process starting with low-cost methyl salicylate.6... 

Distillation is one of those unit operations that assumes its importance based on the scale of operation. Clearly, distillation is one of the most important operations in a petroleum manufacturing plant where separations of closely boiling liquids require sophisticated distillation column design, built upon detailed theoretical plate determinations, material of construction issues, and secondary distillation requirements. In the pharmaceutical industry, the recovery and recycle of a solvent (versus incineration) depends on process scale. Further insight into the problems that might be faced in recovering solvents (and reagents) is provided in the section entitled Dilevalol Hydrochloride Development of a Commercial Process. ... 

The use of a Kraus-Maffei type of containment unit is described in the case study entitled Dilevalol Hydrochloride Development of a Commercial Process (q.v.). The... 

CASE 1 DILEVALOL HYDROCHLORIDE—DEVELOPMENT OF A COMMERCIAL PROCESS... 

Testing the concept required the preparation of pure samples of each of the four enantiomers. These were prepared by Gold et al.3 and Chemical Development using classical resolution and chiral synthesis methods. It was quickly found that the RR enantiomer, later named dilevalol, was virtually free of a-adrenergic receptor blocking activity and also possessed superior vasodilator properties versus labetalol. 

The possibility of separating dilevalol from labetalol was considered as an option at the commencement of the dilevalol project. However, it quickly became clear, from work carried out in both Research and Development, that this approach might not be a viable option. Although the racemic pairs (RR + SS and RS + SR) were separable by crystallization, and although the optical resolution of the RR and SS enantiomers could be achieved through salt formation with a chiral acid, the direct yield of dilevalol was less than 20%. Nevertheless, it was recognized that if the recovery and recycling of the waste streams from the physical and optical resolutions could be carried out efficiently, considerable economies would be obtained (Scheme 1). 

The above realities, along with the realization that large quantities of dilevalol would be needed quickly for the Toxicology, Clinical, and Pharmaceutical Development programs, led Research to propose a chiral synthesis for the initial supplies. The process identified was based on the use of a labetalol intermediate and analogous chemistry to that used in the subsequent manufacturing steps for labetalol. 

Synthesis of Initial Supplies of Dilevalol for Cardiovascular Therapy Team Programs... 

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... 

Conformation of CH, 1 CHCfjHg HN CH(CH2)2CeHg ch3 Stereoisomer Analysis of Crude Dilevalol Acetate Stereoisomer Analysis of Dilevalol DBTA Salt Yield of Dilevalol DBTA Salt Based on Starting RR Secondary Amine... 

Reaction of VI with n gave a high yield of aminoketone VII, which when reduced first with sodium borohydride and then with hydrogen Pd/C gave crude dilevalol isolated as its acetate (Scheme 4). The acetate salt was purified by dissolution and crystallization as its DBTA salt. 

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