x chnvcchchnJcchchnJ
Reaction of the Mannich product (112) from acetophenone itself with the Grignard reagent from p-chlorobenzyl chloride gives the carbinol, 113. Dehydration in this case gives the antihistamine pyrrobutamine (114).29 It is not immediately clear why dehydration does not occur in the other sense so as to afford the energetically more favored stilbene.
As a class, analgesics tend to be built around portions of the morphine molecule that, as a minimum, incorporate a piperi-dine ring. The detailed discussion of the chemistry and biologic activity of these compounds is therefore incorporated in that particular section of this volume. Biologic activity, however, cannot be always neatly categorized; there exists a series of narcotic analgesics whose structure and chemistry more nearly fit those of the phenylpropylamines than those of the morphine analogs. The curious reader is asked to skip to that section for a fuller discussion of the rationale for what follows. Suffice it to say for the present that extensive dissection of the morphine molecule evolved the so-called morphine rule. This holds that the structural elements necessary for analgesic activity are represented by the partial structure below.
The first of the analgesic agents to incorporate the structural elements of this rule in an acyclic compound, methadone (119), was developed in Germany during the Second World War. Details as to structure and synthesis were available to the outside world immediately following the end of hostilities only in the form of intelligence reports. Repetition of the putative synthesis revealed that ambiguity existed as to the structure of the final product. The key step, alkylation of the anion obtained from diphenylacetonitrile with n-(2-chloropropyl)-dimethylamine, in fact affords a pair of isomeric amines. One of these can be Imagined to arise by straightforward displacement of halogen by the carbanion (115). The isomeric amine is thought to arise by internal cyclization of the haloamine to the aziridinium salt (117) prior to alkylation. Attack on this charged species by the carbanion at the center most susceptible to nucleophilic displacement will afford the isomeric amine (116) . Reaction of the abnormal alkylation product (116) with ethylmagnesium bromide affords, ■ifter hydrolysis of the intermediate imine, the compound that lumed out to be methadone (119) .30 Similar treatment of the expected alkylation product gives isomethadone (118).30
Synthesis of the intermediate aminonitrile for methadone by .1 r^giospecific route served to confirm the structure. Alkyla-lIon of diphenylacetonitrile with l-chloro-2-propanol affords the ■ilcohol, 120, free of isomeric products (although it is possible here, too, to imagine cyclization of the halide prior to alkyla-lion). The hydroxyl is then converted to the bromide (121) by
+ nc-c-ch2chn nc-c-chch2n
nc-c-chch2n
means of phosphorus tribromide. Displacement of halogen by means of dimethylamine completes the synthesis of an amine identical to 116.31>32 in much the same vein, displacement of halogen on 121 with morpholine gives the amine, 122. Elaboration of the nitrile to the ketone affords the analgesic, phenadoxone (123).33 This same scheme, starting with displacement of halogen by piperidine, gives dipipanone (125).34
Omission of the side chain methyl group also leads to an active analgesic, the potency of which is somewhat less than half that of the parent. Alkylation of the familiar nitrile with N-(2-chloroethyl)dimethylamine gives the amine, 126. Reaction with
ethyl Grignard reagent leads to normethadone (127).35
- 126 127
Modification of the ketonic side chain is also consistent with retention of analgesic activity. Thus, reduction of methadone with lithium aluminum hydride affords the alcohol, 128 (apparently as a single diastereomer). Acetylation gives acetyl-methadol (129).36
Hydrolysis of the nitrile in 130 (obtained by an alkylation analogous to that used to prepare 126) affords the acid, 131. tsterification with ethanol affords the analgesic agent, norpipa-none (132).3S
Replacement of the ketone by an amide leads to increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135).37 Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone.
Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137).3e It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity.
CH3 ^CH3 VCH
CH3 ^CH3 VCH
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CHAPTER 6
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