TH . SYNTHESIS OF SOME DIALKYLAMMOETHYL NAPHTHYL ETHERS Thesis for the Degree of M. S. MICHIGAN STATE COLLEGE Philip Johnson 1948 t": I" M p.39 If, a «9M WZWWWWXS \\\\\\\\\\ / _ JIM/9‘;L II AP . I‘ L111 m . UHIVer 31W 2' 4 e i 4i i" V Th: E.“ i! SYNTHESIS OF SCME DIALKYLAMINOETHYL NAPHTHYL ETHERS By PHILIP JOHNSON A THESIS Submitted to the School of Graduate Studies of Michigan State College of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1948 Tb». 5:23:21 ACKNOWLEDGMENT The writer wishes to express hie appreciation to Doctor Robert M. Herbet, for his counsel and guidance during the course of this work. #*****#* **#*#* **8* *1! up 331643 CONTENTS Page INTRODUCTION...0.0.000.00......OOOOOOOOOOOOOOOOOOOO 1 HISTORICALOOOOOOOOO...0..0.0.0000...OOOOOOOOOOOOOOO 2 DISCUSSIONCCCOOOOOOOOO.00.00.00.000.IOOOOOOOOOOO... 12 EXPERITENTALOO.0OOOOOOIOOOOOOOOOOOOOOOOO0.0...0.... 18 1. Chemical Reagents....................uu. 19 2. .P-Naphthoxyethyl bromidaeeeeeeeeeeeeeeeee 20 3. J'Naphthoxyethyl brom1deeeeeeeeeeeeeeeeee 21 4. P—Morpholinoethyl P-naphthyl other. . . . . . 23 5. p—Piperidinoethyl -naphthy1 ether...... 25 6. p-Diethylaminoethyl P-naphthyl ether.... 26 7. Piperidinoethyl oL-naphthyl other. . . . . . 27 8. p-Moroholinoethyl cL-naphthyl ether. . . . . . 28 9. f—Di ethylaminoethyl cfi-naphthyl ether . . . . 29 10. fi-Dimethy 1ami noethyl -naphthyl other. . . 30 ll. P-Dimethylavninoethyl cL-naphthyl ether.. . 31 12. MethiOdide derivatiVOSeeeeeeeeeeeoeeee.eee 32 ABIALYTICAL...OOOOOOOOOOOOOOOOOOOOOOO00.00.00.000... 33 Stn'fl-m-RYOOODOOOOOOOOOOOOOOOOOOCOOOOOOOOOOIO00.0.0... 36 LITERAFIRE CITEDOOOOOOOO0.00.00.00.00.0.00.00.00.00 37 'I we a» INTRODUCTION The prOgress that has been made in the elucidation of the struc- ture of organic compounds has permitted the investigation of the structure of pharmacologically active compounds. Due to inability to commercially duplicate the natural products, or because of the desire to improve upon them, efforts have been directed towards the prepara- tion of structurally related compounds in the hope that there was a relationship between chemical structure and biological activity. Such relationships have been found and in many instances have led to the synthesis of important new drugs. Today intensive efforts are directed toward this same goal. This thesis describes the preparation of some dialkylaminoethyl naphthyl others (I) which are structurally of a class of compounds (II) that contains many biologically active members. ClOH7OCH2 CHZN C A-M-C-C-N ( I II In general, A represents an aryl group, and M is a hetero atom. Drugs having this skeleton, or one very similar, have been useful as anti— histaminics, sympathomimetics, anaesthetics, and antimalarials. It is believed that compounds of structure I, if active at all, can be re- garded as potential local anaesthetics, and they have been discussed from that viewpoint in the next section. However it is to be empha- sized that only laboratory or clinical tests, which have not yet been conducted, will determine the compounds' usefulness. HISTORI CAL Ti“, 53!! PART I Local Anaesthetics According to Chen and Scott (1) local anaesthetics are drugs which interrupt the conduction of pain impulses at the periphery, in contrast to general anaesthetics which block the pain sensation of the brain by depression with loss of consciousness. Of course, most local anaesthetics do not act by blocking the sensation of pain exclusively, but rather through the deadening or elimination of any sensation in the localized area. Attempts have been made by man for several thousand years to induce local anaesthesia. The earliest known form.was by the use of pressure, a method that was in use until comparatively recent times. Too often the procedure resulted in anemia or permanent paralysis. Another physical method that was practiced was spraying the skin with ether or some other volatile liquid that would evaporate fast enough to freeze the skin. Perfect anaesthesia was achieved by this method only after a painful period of initiation. Damage to the frozen skin.was one of the unpleasant results of the method. The real history of local anaesthesia begins with Karl Koller's first report (2) of the use of cocaine in opthamological practice and surgery in 1884. This followed by twenty-four years Niemannfis discovery of cocaine (3) in coca leaves. “rzw seas The alkaloid cocaine is known to be habit forming and quite toxic. Solutions of it are unstable to the action of microorganisms and cannot be purified by boiling because of decomposition. Accord- ingly, chemists have spent much effort seeking compounds that might possess the useful physiological properties of cocaine without its undesirable features. After the elucidation of the structure of cocaine by Willstatter (4) in 1901-1903, a large number of compounds structurally related to cocaine were prepared and tested in order to determine what part of the structure of cocaine is responsible for its activity. From the mass of evidence presented, Hyman (5) concluded that the active group in cocaine is the alkylaminoalkyl benzoate grouping which is indicated in the formula for cocaine: H20 EH CH—COOCH3 i . - I :T 033 CH ococans: 1 1 H2 {.CE‘__-_____F2 _______ .i This prediction by Ryman, was partially responsible for the dis- covery by Einhorn (6) of novocaine (procaine), a powerful local anaesthetic only one seventh as toxic as cocaine. II -g0CH2CH2N(CZH5)2 Novocaine ( 43-diethylaminoethyl-p-aminobenzoate) This compound is probably still the most widely used injection anaesthetic, although it is ineffective as a topical agent. -4- Until recent times, most investigators have been guided by a consideration of the structure of novocaine and the conclusions of Pyman;. and most of the compounds having local anaesthetic activity are structurally related to cocaine and novocaine. Hirschfelder and Bieter (7) have given a rather thorough review of the field (1931) and list over five hundred references. In recent years many compounds having only a part or none of Ryman's basic structure have been reported in the literature on local anaesthetics. Such unrelated substances as phenyletnyl alco- . hol, hexylamine, alkylamdncalkyl esters of trichloroacetic acid, some amino alcohols, and even some sterols have local anaesthetic properties. From this, we may conclude that Pyman's hypothesis is in need of revision. ' Erdtman and Lofgren (8) have made an extensive compilation of compounds which show'local anaesthetic action. The list includes a number of nitrogen free compounds which are of theoretical inter- est only. The nitrogen containing compounds listed include many examples of the following types: 1. .Amines 2. Aminophencl ethers 3. Aminoalcohols 4. Aminoketones 5. Aminoethers 6. Esters (This group comprises the greatest number of local anaesthetics) -5- 7. 8. Amides Heterocyclic compounds More recently Lofgren (8b) has proposed a general scheme to account for the local anaesthetic action of a greater range of com- pounds than can be accounted for by the original hypothesis of Pyman. According to Lofgren, the anaesthsiophoric principle in the vast majority of local anaesthetics is built up according to the following picture: LIPOPHILIC CENTER--INTERMEDIATE CHAIN-~HYDROPHILIC CENTER Lofgren believes the following factors are desirable in thera- peutically applicable compounds: (1) The lipophilic end should have an aromatic structure. (2) The intermediate chain should consist of a hydrocarbon (3) residue joined to the aromatic structure through either an ester or amide group, which serves to increase the activity. The ester or amide group may be replaced by the ether oxygen, the amine nitrOgen, or the ketonic carbonyl group. The hydrophilic and should consist of a tertiary amino group (dialkylamino, piperidyl, etc.) although secondary amines may also be used. As a rule certain limitations in the size of the alkyl groups on the amino nitrogen should be observed. (4) The "balance” between the lipophilic and hydrophilic ends is of greatest importance. 'Whether or not the above scheme will be of much use in devis- ing new local anaesthetics remains to be seen. Lofgren does not explain in this article what factors determine ”balance", or what the term is meant to imply. The compounds prepared in this research are dialkylaminoethyl naphthyl ethers having the following structure: / 00H2 CHZN \ III CO IV A number of local anaesthetics with the naphthalene nucleus \OCHCHN’ 2 2‘ have been prepared by other investigators (9) (10). Esters of aminonaphthoic acid (9) reportedly showed an activity comparable to cocaine and the toxicity was also said to be less. No references were found in the voluminous literature on local anaesthetics to the dialkylaminoalkyl naphthyl ethers. It is reasonable to expect that compounds of structures III and IV should be active if one compares their structure to Niemann's basic picture (1). Everything is in- tact except that the ether link replaces the ester group. Struc- ture III may be redrawn as follows: we“ 6 \Cgéwfl H 'V This structure with an amino group in position six would be almost identical to that of novocaine (III). If these structural similarities are significant it should lead one to predict that the c10H7OCHZCHZBF —Bb-CIOH7OCH2CH2N\R Clemo and Perkin (16) prepared dimethylaminoethyl .P-naphthyl ether by heating fi-naphthoxy ethyl chloride and dimethylamine in a sealed tube for sixteen hours at 120° - 140° C. To prepare the intermediate chloride, they treated p—toluenesulfonyl chloride with ethylene chlorohydrin and allowed the ,P-chloroethyl p-toluene- sulfonate so formed to react with P -naphthol. They reported an overall yield of 82% for the two reactions: (1) p-CH3C6H4SOZCI 4. CHZOHCHZCl qp-cnscsfiétsozocnzcnzm (2) P-CmH7ONa 4. p-CH3C6H4SOZOCHZCH2C1 #13 «11037003203201 Although Clemo and Perkin needed two steps to prepare the intermediate, from the standpoint of yields their method is excel- lent. Kirner and Richter (17) also prepared P-naphthoxy ethyl chloride in two steps. By interaction of .P-naphthol and ethylene chlorohydrin the corresponding alcohol was obtained and this was TL“ ‘33! converted to the chloride by means of a Darzens reaction.using pyri- dine and thionyl chloride. They reported fair yields. The reaction between an alkyl halide and a secondary amine is frequentky employed for the preparation of tertiary amines. The most straightforward procedure is to mix the reagents and heat them in a sealed tube (16). But it has been demonstrated frequentky that better yields of a purer product can be obtained using milder conditions. The method used by Cromwell (18) in the preparation of some tertiary amines is essentially the method adopted in this research. According to this method, excess secondary amine and the alkyl halide are dis- solved in benzene or toluene and heated until the reaction is com- plete. Ether is added to the cooled solution to precipitate complete- ly the secondary amine salt which is then filtered and recovered. The excess secondary amine is then distilled from.the reaction mix- ture. Since the hydrochloride is usually desired, the tertiary amine is dissolved in ether and treated with anhydrous hydrogen chloride to precipitate the salt. -11.. w A. 7:“! DISCUSSION -12- Preparation of the Intermediate Compounds The alpha and beta naphthoxy ethyl bromides were prepared by addition of sodium hydroxide to a boiling mixture of ethylene bro- mide, naphthol, and water. The reaction did not proceed until the sodium hydroxide was added, indicating that it is correctly written \ 0’ ocnzcnzsr +CHZBrCHzBr ——> 4- Br" By adding base slowly to the other reagents, an effective ex- as follows: cess of ethylene bromide was maintained and this precaution to- gether with the use of an excess of ethylene bromide should serve to minimize the formation of the dinaphthyl ethylene ether. \ OCHZCHzBr-l- 0N1" '/ I \ ocnzcnzo / \ / The course of the reaction, which usually took six to eight hours,was followed by titrating small aliquots of the reaction mix- ture with standard acid, using a methyl orange indicator. The method of preparation described above was chosen. because the bromoethyl naphthyl others could be prepared in a single step. Also it seemed desirable to prepare the bromoethyl ethers as inter- mediates, since they should condense with secondary amines more readily than the corresponding chloroethyl ethers which are obtained by the alternative methods previously mentioned. However, the naxi- mum yields obtained, which were 40% to 50% of theoretical, and the -13- tedious procedures required to separate the desired products from the reaction mixtures, did not justify the selection. After most of the experimental work was completed, it became apparent that better overall yields of the'fB-chloroethyl naphthyl ethers could be obtained by an adaptation of the technique of Clemo and Perkin (16) and that the chloroethyl naphthyl ethers could be converted into the dialkylaminoethyl naphthyl ethers without undue difficulty. Preparation of the Tertiary Amines The interaction of the secondary amines with the naphthoxyethyl bromides in benzene or preferably in the higher boiling toluene, which increases the reaction rate, was usually complete in a matter OCHZCHZBt+ZHNRZA>iillullil Two moles of amine are stoichiometrically necessary for each of hours. OCH: “2% {-HNR oHPr mole of halide, and a slight excess over this amount was used. (In reactions where quaternary salt formation occurs readily, a three or four fold excess of secondary amine may be required.) By adding ether to the benzene or toluene solution, the secondary amine salt was precipitated completely, and usually in almost pure condition. The amount of secondary amine salt formed can be used to estimate the extent to which the reaction has proceeded. Due to the comparatively large difference in their molecular weights, -14- the unreacted excess of secondary amine was separated from the ter- tiary amine by evaporation of the solvent under reduced pressure, leaving the tertiary amine relatively pure. The preferential precipitation of the secondary amine hydro- chloride depends upon a marked difference in the base strength of the secondary and tertiary amines involved. The first satisfactory explanation of phenomena of this type was made by Brown (19) when he explained the anomalous base strength of the methylamines. It is a known fact that methylamine is a stronger base than ammonia. This is attributed to a “positive inductive effect" which results from the introduction of a methyl group into the ammonia molecule. The greater basicity of dimethylamine as compared with monomethylamine can be explained in the same way. However, trimethylamine is an appreciable weaker base than the other two methylamines. Brown attri- butes this to steric strain, arguing that it is reasonable to assume that in the free trimethylamine the groups are not at the ninety degrees that theoretical considerations predict, but instead they are at a greater angle because of physical space requirements of the sub- stituents. Addition of a fourth grmp forces all of the groups about the nitrogen atom to crowd closer together, setting up a (steric) strain that reduces the stability of the addition compound. Brown refers to this type of strain as "B-strain," to distinguish it from the steric type of interference which depends upon the space requirements of both components of the addition compound, "F-strain.“ -15- "B-strain? can be predicted for other tertiary amines, includ- ing the compounds prepared in this research, and it can be expected that the effect would be further enhanced because the groups around the nitrogen atom are larger. The experimental evidence seems to confirm.this theory. A number of modifications of the general method of preparing the tertiary amines were necessary because of individual differences in the properties of the secondary amines. For example, reactions with dimethylamine, which is a gas at room temperature, were carried out in a steel bomb. Diethylamine reacted with the naphthoxyethyl bromide only slowly in benzene solution. It reacted satisfactorily, however, in vigorously refluxing toluene or, alternatively, in a steel bomb. Preparation of Derivatives The addition of methyl iodide to each of the eight tertiary amines that were prepared gave either an oil that could be coaxed into crystallizing or also gave a white crystalline solid directly. The derivatives were recrystallized from alcohol-ether. AlternateLy cooling and scratching the sides of the test tube was often essen- tial to induce crystallization. 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