Anesthetic intermediates

J. Bartek etal, US Patent 6,673,957 (January 6, 2004) Assignee Lonsa AG Utility Anesthetic Intermediate... 

Thus, acylation of 3(W,iV-dibutylamino)propanol (39) with p-nitrobenzoyl chloride affords the intermediate, 40. Reduction of the nitro group gives butacaine (41), an agent equipotent as cocaine as a topical anesthetic. 

Benzoylation of 3-chloropropan-l-ol affords the haloester, 52. Condensation of this intermediate with the reduction product of a-picoline (S3) affords the local anesthetic, piperocaine (54)... 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

Treatment of 2,6-dimethylaniline (121) with phosgene and triethylamine affords the corre-S]ionding isocyanate (122). Condensation of that reactive intermediate with N-isopropylpropyl-cne-1,3-diamine leads to formation of urea 123. This product, recainam (123), acts as membrane Stabilizing agent and thus exhibits both local anesthetic and antiarrhythmic activity [30]. 

The ultra-short-acting barbiturates include methohexital sodium (Brevi-tal) and thiopental sodium (Pentothal). These agents are used as anesthetics and are administered intravenously. Barbiturates with short-to-intermediate duration of action are used for their sedative-hypnotic effect in the treatment of anxiety. These medications include amobarbital (Amytal), butabarbital (Butisol), sodium pentobarbital (Nembutal), and secobarbital (Seconal). 

In anesthetized rats, amphetamine causes dose-dependent changes in neostriatal unit activity. Spontaneously aetive neostriatal cells are uniformly inhibited at low (<2.0 mg/kg, IP) doses. At intermediate doses, an initial exeitation precedes the inhibition, and, at high doses (>5.0 mg/kg, IP), the predominant effect is excitation (Groves and Rebec 1976). Regional differences in the direction, magnitude, and duration of the response of neurons in the neostriatum exist (Rebee and Curtis 1983). 

Shulman, M., and M.S.Sadove. 1967. 1,1,1,2-Tetrafluoroethane an inhalation anesthetic agent of intermediate potency. Anaesthesia Analgesia 46 629-633. 

FIGURE 4.62 Oxidative dehalogenation of halothane to form areactive acid chloride intermediate and structures of other anesthetics that can form similar reactive metabolites. 

Chloroform is used primarily in the production of chlorodifluoromethane (hydrochlorofluorocarbon-22 or HCFC-22) used as a refrigerant for home air conditioners or large supermarket freezers and in the production of fluoropolymers (CMR 1995). Chloroform has also been used as a solvent, a heat transfer medium in fire extinguishers, an intermediate in the preparation of dyes and pesticides, and other applications highlighted below. Its use as an anesthetic has been largely discontinued. It has limited medical uses in some dental procedures and in the administration of drugs for the treatment of some diseases. 

Uses Intermediate for production of tetraethyl lead and ethyl cellulose topical anesthetic organic synthesis alkylating agent refrigeration analytical reagent solvent for phosphorus, sulfur, fats, oils, resins, and waxes insecticides. 

Uses Extraction solvent insecticide, oils, and fats chemical intermediate for 1,1,1-trichloroethane in rubber cementing, fabric spreading, and fire extinguishers formerly used as an anesthetic organic synthesis. 

Intravenous administration of 4—lOmg/kg produced bradycardia and an initial transient hypertensive effect in the anesthetized dog. Toxicity is thought to occur from the decomposition of decaborane to a stable intermediate that in turn inhibits intracellular pyri-doxal phosphate-requiring enzymes. ... 

Uses. Cleansing agent degreaser solvent for plastics, oils, and fats grain fumigant chemical intermediate formerly used as an anesthetic... 

Uses. Degreasing solvent dry cleaning and extraction chemical intermediate limited use as an anesthetic and analgesic... 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

The basic components in the structure of local anesthetics are the lipophilic aromatic portion (a benzene ring), an intermediate chain, and the hydrophilic amine portion (Fig. 27.1). The intermediate chain has either an ester linkage from the combination of an aromatic acid and an amino alcohol or an amide linkage from the combination of an aromatic amine and an amino acid. The commonly used local anesthetics can be classified as esters or amides based on the structure of this intermediate chain. 

Model structure of local anesthetics showing aromatic portion, intermediate chain, and amine portion. 

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