128 773 PORTHOJOLYL-‘PETHYL' 4~ METHYL" S-PYRAZOLONE Thesisfor the Degree 0‘ I“. 3. MICHIGAN STATE COLL308 Albert E. Timreck 3947 TH 33!. I «‘ I; Um‘vm at 5;: Hr“. "$1 ‘3?- L‘M‘E 'J-"JV a ' I.) s .13", ; 1 \ 1 II' “a ’Q - . A 1‘! hi‘ya ' i, I ’V‘ # TWI‘ 'l I ' P ~/ I § 1" 2.53“: .1 m ‘-‘ 1-Ortho-Tolyl-3Jth114-hthyl-S-rmso lon- locum-To 1: 1-3-Eth’1-4-Iothy 1-5-Pyraso1ono A Theall Submitted to the Faculty of H16 higan Stu“ 0011030 In partial mltlllmnt. of th. requirements for thc demo of nuts:- of Solemn. 3! 11b.” 3. Tim-oak Jun. 1947 ACKNOWLEDGMENT It is with appreciation that 1 tot. this opportunity to express I: thsnks to Dr. R. 0. Huston for his sssistanos snd snoourngonsnt in carrying out this work. 15.3.1. ' 331-590 -1- REVIEW OF THE LITERATURE 1. Constitution of the Pyrasols Group The pyrazols group ia made up of those compounds having a five-neabered cyclic systea of two nitrogen and three carbon atone arranged as follows: 23 5 3 # Pyrazole itself is a 1.2-diasoie. The structure or the pyrasole ring has been.definite1y established by the investigations of many workers. Outstanding was the work done by Lu Knorr and his coworkers (1.2.3.‘). Pyrazole may be regarded as a derivative of pyrrols in which one of the nothine groups adjacent to the NH group has been replaced.by nitrogen. NH - H H H H H H Pyrrole Pyrasole Because of this structural relation. Xnorr suggested the use of the sane nomenclature for derivatives or pyrazole as are used for pyrrois derivatives. The dihydrOpyraaoles then are known as the pyrazolines and the tetrahydro-derivatives as the pyrazolidines. 1N8 NH ’//§E\ zit/\nfib‘ i“? P’ ('8, SH 3‘ H 52 H21_———-!Hz Pyrasols Pyrazoline Pyrazolidine P‘. u \f.’ The positions of eubstituent groups are indicated by nun- bering the members of the ring starting with the iaino nitrogen atom , as ehown above, thus giving the hetero-atone the lowest possible numbers. ‘ Knorr suggested the formula for pyrazole shown above based on his work with l-phenyl pyrasols (5). later Knorr and co- workers showed that l-phenyl-B-nethyl pyraaole and l-phenyl- S-asthyl pyrazols gave the sans methyl pyrazole and concluded that In pyrasole itself the three and five position are equi- valent. The 3(5)-nethyl pyraaols then is a nixture of the two desectropic for-s. Knorr assumed that the l-hydrogen is not permanently link- ed to one nitrogen stone, but may alternate to the other nitro- gen with e readjustment of the double bond. Ti“ ““\-,, “\L °\éa I. II. According to the modern conception, the rearrangement is not a simple tautoseric shift of the hydrogen stow. Actually the rearrangement is the same as that encountered in the inroa- tion of pyrrolidine froa pyrrole and involves the splitting off of a proton followed by shift of the electron pair and addition of a proton. .there cannot be then two ssthyl pyramles with the formias: R H _ GH3U: and ' fin“) II‘here are only three possible isomeric methyl pyrssoles: ~03} R 83 fi \\\fifi ” EH fi//\\\flfl HC—————CH CH30-——- H 80 ~03} lpnethyl 3(5)-Iethyl h-nethyl pyraaole pyrasole pyrasols Pbr these reasons Knorr suggested the structural formula of the 3(5)-pyrasols to be: his conclusion has been confirmed by the fact that esthyl pyrasole can act as either a 3- or 5-methyl.pyrasole. From the above discussion it can be seen that replacement of the iuino hydrogen atoa by a substituent group sakes the 3- and 5-positions no longer equivalent. 3-0585 N-Géfis ‘H CH3 8 l-phenyl-3-nethyl l-phenyl-S-eethyl pyrasole pyrasols Claisen and Roosen obtained these isomeric pyrasols derivatives by condensing phenyl hydrazine with cxymcthylsns acetone (6,7). Although pyrasole and pyrrole are similar in their struc- tural formulas. they are quite different in their chemical pro- parties. Pyrasole is much more stable and has a more basic character than pyrrole. In its chemical properties, it resea- bles the pyridine bases. Pyrasols is a weak secondary base which has a definite aro- natic character. Knorr has listed a number of preperties which show its aromatic nature. 1. It is sulfonated by fuming sulfuric acid to pyrasole sulfon— ic acid. 2. In its halogen derivatives, the halogen atom is held even lore firmly than in benzene derivatives. W 3. Pyrasole is nitrated readily with concentrated nitric acid. As with.aroeatic nitro compounds. h-nitro pyrasole and its deri- vatives can.be reduced to the corresponding amino coapounds (9.21). A. Amino pyrasols reseablss the aromatic bases in its behavior. It gives a color reaction with a solution of bleaching powder, and it is readily dissatiaed. 5. Disco pyrasolss couple with phenols to give aao-dyes. their salts are lore stable than those of the aromatic diasoniue cos- pounds in aqueous solution, giving off nitrogenlonly after pro‘ longed heating at higher temperatures. The diaao pyraaolss do not, however, give the usual ”diam-reactions.” 6. Pyrasoles show the same remarkable stability to oxidising and reducing agents as does benaene. 7. Pyrasolone, or 5-hydroxy pyraaols, has a pronounced phenolic character. 8. Hoaologues of pyrasole resemble those of benzene in being readily oxidised to the corresponding carboxylic acids. Pyrazole can also be acylated, bensolated, or converted in- to derivatives of urethane and urea. II. Synthesis of Pyrasole and Derivatives Pyrasols itself was first prepared by E. Buchner in 1899 by heating 3:k:5-pyrasole tricarboxylic acid (8). It was later prepared by Balbiano by heating epichlorhydrin with hydrazine hydrate (9). Yen Pechsann obtained pyrezole by reacting acety- lene with diaso methane. Claisen accomplished the synthesis by treating the acetal of propargyl aldehyde with hydrasine (10). According to Knorr the best method for the preparation of pyra- sole is the decarboxyiation by prolonged heating of 3:5epyrasols dicarboxylic acid. Knorr in 1883 prepared the first pyrazole derivative, pre- paring l-phenyl-B-methyl-S-Pyrazolone by the action of phenyl hydrazine on acetoacetic ester (11.12313). He later'prepared the ethyl.ester of l,3-diphsnyl-5-methyl pyrasols-k-carboxylic acid by the reaction of benzoylacetoacetic ester on phenyl hy- drazine (1,14). Knorr described a number*of syntheses for pyrezolone deri- vatives, such as: (a) the condensation of fi-keto acids with hydraaine, (b) the reaction of g-diketo compounds of the gener- al formula R'-CO-CHR'-CJR" with hydrazines, (c) the condensation cf’hydrasines with unsaturatedaldehydes and batches of the type shoe-caucus" and ace-cancels". and (d) by boiling the phenyl hydrazonee of unsaturated aldehydes and ketones having a double bond in theCKpposition with glacial acetic acid (1). Kany other methods have been described for the preparation of pyrasole derivatives, such as: ‘ W l. Buchner prepared derivatives of pyraaole by the reaction of diazoacetic ester with various unsaturated compounds (15). -6- a. By the reaction of diazoacetic ester with acetylene dicsrboxylic acid to give the methyl ester of pyrasole tricar— boxylic acid. b. By the action of diasoacetic ester on ethylene deri- vatives, such as the ester of fumeric acid to form pyrasoline tricarboxylic ester. c. Combination of diasoacetic ester with the ester of saturated and unsaturated halogen-substituted esters, such as dibrono prepionic ester to give pyrasole dicarboxylie ester. 2. Bischler prepared pyrasole derivatives by the action of diasonium saltsflpn substituted acetoacetic esters (16,17). “Pals“. "' . ‘ 3. Claisen prepared phenyl pyrnzole by the treatment of the acetal of propargyl aldehyde with phenyl hydrazine (10). 4. Fischer and Bulow prepared diphenyl methyl pyrasole by the reaction of phenyl hydrazine with benzoyl acetone (18). 5. Olaisen and Reason obtained the phenyl methyl pyrazolss by condensing oxymethylene acetone with phenyl hydrazine. They prepared derivatives through the condensation of acetone oxalic acid with phenyl hydrazine, and also by the condensation of the aldehyde of acetoacetio ester with phenyl hydrazine (6,7). 6. Knorr and yacDonald prepared phenyl methyl pyrasole by the condensation of hydrazine hydrate with cry-ethylene acetone (2). 7. Certain hydrasones heated with acid anhydrides yield pyra- sola derivatives, sceto phenyl hydrazone with acetic anhydride giving 1-pheny1-3,5-dinetbyl pyrarole. 8. Stoermer and Martinsen prepared pyrazole derivatives by distilling the oxygen derivatives, such as the pyraaolones, with sine dust, phosphorus pentasulfide, or phosphorus tetra- broaide (19 ) . -7- In general. compounds containining two 00 groups or a Go and 0003 group in E-position to one another or two doubly-linked carbon atoms adjacent to a 0003 or CO group react with hydra- zines to give pyrazole derivatives (20). g”, -8- III. Constitution or the Pyrnzoloncs There are three ketonic derivatives of pyrnzoline which can be divided into two classes: the 4-derivntives or true ketoncs as derived from hate—acids, one the 5- and 5-derivatives or ryrnzoloncs which are the cyclic acid amides (l). wn AA 2 Q Eopyrezolone é-ketOpyrezolinc S-Fyrczolone Pyrczolone bears the same relation to pyrazolinc as gy- ridone does to pyridine. 1 CB 0 E 4.1 g} a. '. it Fyrczolonc Fyrnzoline Pyridone Iyridine Knorr established the constitution of pyrezolone by dis- tilling phenyl methyl-t-pyrnxolone vith zinc dust to obtain a weak base tith c composition Clofilfirg. The base so obtained resembled the pyrnzcle bases. Its salts are deconp sed by water. The rock hose on reduction with sodiun and alcohol yes changed into a base rich in hydrogen which resembled the pyrczoline hoses, giving n violet color with oxidizing agents (1). Fncrr shoved than that the base obtained by the reduction or the pyra- zolone to be 1-phenyl-3-nethyl-gyrczole uith the forfluln: -9- By the method of its fornstion, the origin of the pyrezolonc from the pyrezole group was shown. The methylene group of ecetoacetic ester is found still unchanged in the phenyl methyl ryrezolone. The oxygen in the pyrezolone cannot be combined as a hydroxyl or ketonic oxygen as it is inactive and must occur in a form similar to the acid amides. The phenyl methyl pyrszolone contains, then, no more hydro- gen which could combine with nitrogen. The pyrazolone can be methylated by treatment with methyl iodide giving, undoubtedly through the nitrOgen atom, the methylated bsse, entipvrine. In the formation of the sntipyrine, though, the molecule under- goes a radical change, the antipyrine no longer containing a methylene group but rather a methine group. This change in the molecular structure lesd‘Knorr to a false conception of the antipyrine molecule. From the above considerations it was evident thut the ten hydrogens of the phenyl methyl pyrezolone were distributed as follows: five on the phenyl group, three on the methyl, and tvo on the methylene group from the eceto acetic ester. There were, then, only two possible formulas for the phenyl methyl pyrezolone: Kc 6H 5 I"? -C 617.5 1' -C}13 H30 -————CH; ! " 0‘ in In II. The choice between these two formulas degends upon decid- ing which is the more probable formula for the phenyl-hydrszone or eceto acetic ester: -10- 615:5 01:31 - ‘31 0515513134520: or J , kc): CH;;CUOCEII5 Lifid 3200001135 1. 2. The situation here is the same as presented by the phenyl~ hydrazones of the aldehydes and ketones for which there are the same types of possible formulas: 015:5 05525151 - 1TH C§f5TTI{-if” ’ or \c< 01:3 E30” (II-Iii 1.. 2. Acetone phenylhydresone If the phenylhydrazones have the formula represented as 1, then.1 would be the formula for the phenyl methyl pyrazolone; it their structure is shown by 2, then 11 is the formula for the pyrazclone. According to E. Fischer, the ketone and aldehyde derivatives of primary as well as the unsymmetrical secondary hydrazines react under the proper conditions in a manner similar to the formation of indol derivatives (32). C (3HSN-F:C\ 0 ”E4 -CIT3 + 137.5 CH3 CNS 5: -CH3 Acetone methyl phenyl- Dimethyl indol hydrazone It is obvious then that in both classes we have the same types of linkages in the hydrazine derivatives. Methyl phenyl hydrazone Phenylhydrazone of of acetone acetone The primary hydrazines and the unsymmetrical secondary hy- drazines, then, react in the same way with aldehydes and ketones -11- at low temperatures. The symmetrical secondary hydrazines re- act with aldehydes at high temperatures and vith ketones with difficulty (23 . From the above considerations, it seems most probable that the formula for the phenylhydrazone of aceto acetic ester is formula 1 . : /CE:5 - ' 7‘ canon-14‘ 1-.- I CrgCOOCghs Knorr on the basis of these facts rejected the carbazine structure for the pyrazolone and accepted fornjla I. for phenyl methyl pyrazolone: fiv—Cgl-‘Eb‘ h ' 5:0 H T CHE-C ——~ 0E2 Knorr stated that l-phenyl-5—methyl-5-pyrazolone may exist in three desmotropic forms, and called the phenomena "double tautomerism" (5). 239.35 v/KC‘JPS was 1' I“) f! (1-0}: :20 GEE ’52 CH3~C—-———LH CH3 ~ Methylene form Phenolic form Inine form Numerous attempts have been made to obtain the various desmotropes from reaction mixtures. It would be expected that the methylene and phenolic forms would exist in a regular encl- ketp equilibriuml It was thought possible, though, to isolate the imine form as a distint compound, but only one form of each pyrazolone has been obtained. Only one l~phenyl-3-methyl~$~pyra- zolone has been obtained which has a melting point of 127°C. The preparation of two isomeric l-o-tolyl-Sqmethyl-S-pyrazclone was reported, but further investigation has shown that the come -12.. pound believed to possess the inine structure is actually the condensation product of the pyrazolone with a second molecule of caste acetic ester which.Knorr had reported in his work on the phenyl methyl pyrazolone (1,24). A mechanism.was proposed to account for the formation of the imine form by assuming the reaction of the anal of aceto acetic ester with phenylhydrazinc to form the phenylhydrazone by a simple splitting out of water. Here, of course, the for- mula for the phenvlhydrazone would be different than that given by the reaction of the keto—form of the ester. The explanation would account, hovever, for the difference in the position of the double bond in the imine form (24,25). H /CH5 c... viz-n}: s. + Ha - c ”H ‘cncoocges Phenylhydrazine. Aceto:acetic ester. It seems improbable that the reaction can be explained by this simple mechanism. The reaction probably goes by way of the usual carbonyl addition mechanism. The imine structure of the pyrazolones is found only in those compounds known as the antipyrines. The phenolic form is found in such compounds as the phenyl ethers, esters, and salts of the alkali metals. The methylene form is that structure which gives the py- razole blue t st. The oxidation of phenyl methyl pyrazolone vith ferric chloride or platinum chloride results in the for- mation of pyrssole blue which represents the indigo of the pyrazole series. In chloroform solution, a deep blue color re- sults, and from other solution, violet needles of pyrazole blue are precipitated (1,26). -13- Pyrazole Blue It is apparent that substitution of one of the hydrOgens of the methylene group by certein groups will make the for- mation of pyrszole blue impossible. -14- IV. Synthooio of tho Pyrozolonoo A. Proporotion of the 5-Pyrozolonoo Tho 5-Dyrooolonoo con bo proporod.by tho condonootion of oryl hydroxinoo oitn boto-koto ootoro. In 1883 Knot-r proporod tho firot pyrozolono. proporing 1-phony1-3-lothy1-5-Dflooolono by coneonoing phonyl hydrooino oitb ocotooootio ootor (1.11). to 125 53o. of phenyl hydrazino, 100 goo. of’ocotoocotic ootor ooo oddod ond tho Iixturo thon our-o4 on o otool both. Tho firot rocction coo tho formation of tho phenyl hydrozono of ocotooootic ootor with the olininotion of wator. Ring cloonro woo offoctod by booting ot o hignor tooporotnro oith tho olilo inotion of alcohol. 0 HES-N o=o-c coco - c art-r --c a 635 32 "' on)“: 235 Me 635 ffi‘kfimz 5 Phony]. hydrooino Acotoocotic ootor Phonyl hydrooono of ocotoocotic ootor 3-05 ~65 H 0285 “5 T=O =0 (‘023503’i_ as} a? 7 633 £12 1-Phony1-3-Iothy1- 5-pyrozolonoo 'i'bo olcohol fornod no diotillod oft. tho oixturo coolod, on! tho product ooohod with other. Tho pyrczolono ooo driod in on ovon at 100° 0. and no pnriflod by rocryotoniootion tron bot oator or hot olcoboi. ‘rbo phony]. nothyl pyrozolono ooltod ot 127° C. Knorr ond moon proporod pyrooolono dorivotivoo by tho con- donation of unooturctod ocido of tho ocrylio acid oorioo (Lo. crotonic acid) oith hydroxinoo (26). -15- Potronk ond Krotoohonko propcrod o dinotnyi.pyrooolono by tho 01.1th1011 01' 002 fro. tho acid fox-nod by tho Goad-nation of phonyl hydrazino with nothyl ocotono diccrbonylic ocid ootoru Knorr and [lots proporod.diphonyl.pyrozolono by condonoing phonyl hydrazino with othyl bonzoyl ocotcto {27). 81:01: obtainod l-phonyl-S-Dfl'ooolono by tho oxidation of l~phonyl pyroaolidino with torric'chlorido (28). Knorr proporod tho ortho and porn tolyl ootnyl pyruolonco by tho condonootion.of tho tolyl hydrcsinoo with:ocotooootic ootor. (29) Klouborlproparod tho moto-xylyl nothyl.pyronolono (30). Huston ond.Brighon.proporod.p-xylyl nothyl pyrooolono by tho condonoation of p-xylyl hydrocino with ocotoocotic ootor (2‘). Bloioo obtoinod l-phonylp3~othy1-5-pyrczolono by tho rooo- tion of othyl propionyl ocototo witn.phonyl hydrocino (31). lnorr and Blank proporod l-phonyl-B-Iothyl-Q-othy1-5-Dlrc- solono by tho condonootion of ok-otbyl ocotoocotic ootor with phonyl hydrazino (32). Thoy oloo proporod.l-phonyl-3,#-dinothyl- 5-pyrozolono by booting nothyl ocotoocotic ootor with phonyl hydrazino (33). Knorr hoctod dinothyl ocotoccotic ootor with phonyl hydro- oino to proparo lppbonyl-J,4,o-trinothyl-S-pyrosolono. Emnorling and Kriotollor'proporod l-phonyl—3~othyl-A~nothyl- s-pyrozolono by connonoing othylcispropionyl propionato with phonyl hydrazino (35). Schrootor proporoa.lpphonyl-B-othyl-k-nothy1-5-Plrololono by oondonoing nothyl propionyl propionoto with phenyl hyrozino (36). -15- IV. E. Proporotion of tho 3-Pyrooolonco Hichaolio propcrod l-pbony1-5-methy1-3-Dyrazolono by con- donoing occtoccotic ostcr with ooetyl phenyl hydrazino in tho prooonco of phoophoruo trichloride. To 15 gmo. of ocotyl.phcnyl hydrazine and l) goo. of ocotoccotic cotor, 14 goo. of phoophoruo trichlorido were gradually addod, and tho mixture was refluxed un- til no more hydrogen chloride wao ovolrod. Tho viocouo oolution woo diooolrod in 10% hydrochloric ocid. cooled. and filtorod. Tho ocid woo noutrolizod with annoniuo hydroxido. procipitating tho pyrazolono. The crudo product wao dricd.on o porouo ploto. If tho pyro- zolono woo dork-colored it was boilod with animal charcoal in alkaline solution. The 3-pyrczolone was purified by rocryotolli- nation from olcohol (37). Equationo showing the reactiono involved: is c 0 I -+’ 05H5NH-N830083 -+ P013-—-———9 5’“?- 0000235 Acotoacotic Acotyl phenyl Phoophoruo ootor hydrazido trichlorido 0 NH 0 H fl-H -C 6 5 H 635 H -CH3 (-HQEL, H. ~03} O: .8 O: H Fhenyl hydroxide of Enol form l-fihenyl-S-lothyl- occtoacetic ooter pyrozolono-3 .__.-. - W -17- According to‘Micheelis, the 5— as well as the 5- pyrazolone is produced by this method, but the latter is much.more abundant. In the reaction with.acylated hylrazines, the reactivity is much less than in the reaction of the hydrazines with ketonic oxygen. Knorr and Duden prepared 1,S-diphenyl-o-pyrezolone by the condensation of phenylhydrazine vith cinnanyl acid (26). Bischlor obtained a derivative of l,5—diphenrl-3—pyrazolone by the action of'diezonium chloride on phenyl ecctoscetic ester. Other eubsfituted ccetoecetic esters can be employed (18). Michaelis and Behrens prepared the ortho and gore tolyl methyl-E-pyrazolone by condensing the corresponding ecetyl tol- yl hydrazine with ccetoacetic ester and phosphorus trichloride(5u Huston and Brigham obtained p—xylyi~5dmethyl-3-pyrezolone by the condensation of para-xylyl ecetyl hydrazide with aceto- ecetic ester end phosphorus trichloride (24). Stolz obtained l-phenyl-pyrazolone-fi by heating the ethyl ester of fi-chlorolectic acid with phenyl hydrazine {39) Fichter, Enzensuer, and Uellenberg prepared l-ghenyl-r- methyl-S-pyrezolone by heating the ethyl ester offg-bromo- methacrylic acid with phenyl hydrazine (40). Nicheelis and Brews condenseGCirmethyl ecetoocctic ester with e~scetyl phenyl hydrazine and phosphorus trichloride to obtain l-phenyl—4,5-dimethyl-5-pyrezolone. They also prepared l-Lheryl-S-metbyl-4-ethyl-E-pyrezolone by usingciyethyl aceto- acetic ester (41). Aolors'vzq ojfldbflflda 9 dam at Y: - 18- v. Bonaoyl intern at tho Pyrazolonoa Not prepared the bonzoyl eater of kph-shy1-3cmethyl-S-pyra- solone by tho Schottcanauman reaction, shaking the pyrazolono in alkali aoluticn with an excess of benaoyl chloride. The eater nae purified by recrystallization from alcohol (42). ‘5635 o/Kcsfls "=0 4- ' 06950061-———> 05350 :0 (EH megabit! 0330 l-Phony l-B-methy 1- 1-Pho my 1-2-1). use: 1- s-pyraaolone 3-nthyl-5-pyraaolone let anon-ed that the pyraaolone reacts in the iaine tor- and that the henaoyl residue attaches to the nitrogen to give a hensanide derivative. Hot accused that the addition or bonny). chloride to anti- pyrine taken place in a different aeneo than the addition of alkyl iodidea to antipyrine. -c ci‘ a-c635 635 33$ _ CH3 =0 + 063560C1 ————" 0635 -O CH3AL=CH CBJG K On the other hand, Knox-r believed that the addition of Demyl chloride and alkyl iodides taken place in the can. sense (21). + CH3I ————->' CH3i + ?‘ H 50001—47 CH Deco-0585 C u— H -19- no conclusion has been reached as to whether the‘bensoyl residue is attached to the nitrogen or the oxygen ates, but Inorr's esplanaticn is generally accepted. Iichaelie prepared the lephon:l-S-methyl-Bobenloyl-Jopyra solace by tho achotton-Bsuman,roaction (37). Hichaolis also prepared the bonsoyl esters of ortho and para l-tolyl-B-nethyl-S-pyrecolone by the use aethod (38). Huston and sell prepared the hensoyl esters of p-xylyl- S-Iethyl-B-pyrazolone and p-xylyl~3-aethyl-S-Dyrasolone by shaking the pyrasolones with.bonsoyl chloride in.pyridine solution (25). -20- VI. lethylation of the Pyrssolones - Antipyrino Antipyrins is the methylated base which is obtained in the for- of its hydroiodide when l—phenyl-chethyl-S-pyrasolone is heated to 100° C. in a closed tube with methyl iodide and asthyl alcohol. the satipyriss is liberated by treating the hydrcic- dide with sodius hydroxide. Knorr prepared antipyrins by this ssthod as crystals which after recrystallisation seltod at 113° 0. .-(.29.A3). 4685 1" n-céas =0 _ + 01131 + CHBOH—e‘ ca) :0 033‘ H (:83 H rhscyl ssthyl pyramlons Hydoriodide of or the pyrazolone x‘a “3635 . K-0635 (if!3 3:0 1- HsOH % CH 3:0 L L 0H3 H CH3 __.———--1.s antipyrins (Knot-r) Knbrr established the structure for sntipyrine to he that shown by the formula above (1.32). Antipyrino is a strong acidic base which is precipitated by alkali and forms salts with acids. It has a stab]. sole- culsr structure and can be boiled in vacuus without rearrange- sent. It decomposes, however, when distilled at stsosphsric pressure. Antipyrine is very soluble in water. alcohol, chm-m... , ‘ 1'". tors, and hot toluene and is difficultly soluble in other and I! lip-sin. Knorr also prepared antipyrins by the nethylstion of 1- phenyl-B-osthyl-soothoxyn-pyrasolons. The methylated product -21- was treated with oulturouo acid, and thentho solution was supersaturated with sodiun hydroxide. The antipyrine was ex- treated with ether and recrystallised (S). lnorr obtained the ortho and para tolyl antipyrines by heating the corresponding pyrazolone with methyl iodide and lethyl alcohol at 100° c. (29). Klauber prepared the Iota-xylyl antipyrine (30). Michaelis prepared the 3-antipyrine by oothylating the 1-phenylos-ncthyI-B-plrasolone with aethyl iodide and methyl alcohol. Eb also prepared the ortho and para 3-tolyl antipy- rinse by wetbylating the corresponding 3-pyrasoleses with asthyl iodide and aethyl alcohol. The hydroiodides were dissolwed in water and the antipyrines liberated by treat-ant with sodium hydroxids. The product was extracted with ohlorofora, dried over Caco3. and.purifted by recrystallisation tron ligroin (38). Stola methylated 1-phenyl-h~eethyIFS-Pyrazolone by prolong- ed heating with aethyl iodide and.aethyl alcohol (28). Richaelis end brews prepared 1-pnen31-2,5-d1utny1+ethy1- -. 3-pyrasolone by heating the Sepyraaolone with nethyl.iodide (#2). Knorr methylated 1-phenyl-3,4~diaethySP5-Plrasolone to ob- tain 2,3,d-triaethylpl—phenylos-pyrasolone (4-aethy1 antipyrine) (33.3“. lb also prepared Methyl antipyrine by aethylatica of the corresponding pyraaolone (32). Eaaerlins and Kristeller prepared lpphenyl-are—diaethyl- B-ethyl-S-Pyrflaolone by heating the pyrasolone in a closed tube with eethyl iodide and aethyl alcohol at 110° c. In lethylat- ed.produot was obtained.as crystals with a melting point of 37- 38° 0. and having a boiling point at 18 an. 01' 208-21006. the product was soluble in alcohol, ether, chloroform, and bensene -22- and was ditticultly soluble in water (35) -23- EXPEPJMENTAL PART 1. Preparation of Ethyl-tk-Propionyl PrOpionate The ethyl propionyl propionate was prepared by boiling ethyl propionate with strong sodium ethoxide using the procedure of McElvain (44) . The reaction can be shown by the following equations: EtOYa 0 x 0N3 // r __ CH3-Cflz-C\ Clia-CHSL- + EtO OEt OEt Ethyl Propionate 0138 CBS 0 / \ // CBS-CH24i“ '- + /C-O ---- CE?) W 73-:- 0121: H ® 7 (Eto') 013a $83 0 037a 01-33 0 ,_ ' // (Eto’) \ n // -C'" +011. art a OEt 53" ) om; 0K3 $E3 0 + 0 CH3 0 3: // H ac. n I // Clig-lez- :C—C\ e CH.:5-CI:I2-C—-—C-—C\ ort OEt Ethyl \\ c“: “33 o-Toluidino o-Toluidine hydrochloride + 62350520 + an :1. CH3 3 SCI Renae-Hal 4- as (8:101, + acn‘ cs 2 “ ’ H 3 3 o-Toluidino diasoniuu chloride o-Iolyl hydrazine hydro- chloride ‘ 4-.-u .‘a- To 107 goo. (l solo) of’Obtolnidino sds added 1300 ll. of concontrstod hydrochloric acid, snd tho nixturo sds plscod in on alcohol both and cooled to -#09 c. Ninety grams of othyl nitrito in 100 ll. of alcohol was cooled with dry ins and thon sddod to tho solution of o-toluidino hydrochloride so rapidly so poosiblo oithout tho tonporoturo rising shovo 40° c. Tho rapid addition of othyl nitrite roducos tho tondcncy for tho formation of tho soino-szo compound. A nochsnicsl stirror olininstod locsl owor- hosting. A solution or #50 goo. of stcnnouc chloride in 500 ll. of concentrated hydrochloric acid sss coolod snd sddod slosly to tho dissoniuo chlorido so so to hop tho tcnporsturo bola" 35° 0. Tho hydrosino hydrochlorido oss obtained so light yolloo-ory- stsls. Thoso wore filtered off. dried, snd docosposod with cous- tic potssh (300 goo. por 300 sl.). rho libsrstdd,froo boss wss oxtroctcd with othor and driod over anhydrous sodius sulfnto. Tho other was distilled off. and tho hydrosino puritiod.by froc- tioncl distillation collecting the fraction 110-1250 0. st 5 on. tho yiold was 8# gas. (691). O-tolyl hydrosino has n oolting point of 61-620 0. snd s boiling point range of 915-1150 0. st 3 no. pressuro. 1t crys- tsllisos on condensing so shits noodles in rosottes which turn yollow rapidly. Tho hydrssino is unstablo snd slowly doconposos on,oxposuro to light and sir. It can ho stored for some tioo ss tho hydrochloride. By carrying out tho dissatisotion with sodium nitrite in squoous olcohol and sdding it to the reaction sixturo to hoop tho tooporstnrc down to -20° 6.. it sss possible to obtain tho o-tolyl hydrosino in good yield (55-601). -28- III. Preparation of l-Phenyl-S-Ethyl-4-Methyl-5-Pyrszolone The pyrazolone was prepared in the manner described by Fm- merling and Kristeller, condensing phenyl hydrazine with ethyl- cX-propionyl propionste. The reaction is shown by the following equations: ~05}! 0235 H 8 i is no _ 0\\ l (-HOE) L OSHbNHEHZ -+ ,/c 4H '7 -—-—-1-H c21115 :5 02% 3 Phenyl hydrazine Ethyl ~propionyl Ester Phenylhydrazone prepionste 66:35 (—02H5GHLJ O ————— 43 1-Phenyl-S-ethyl-demethyl- 5-pyrezolone To 22 £333. of phenyl hydrazine was added 32?. gas. ofethyl propionyl pr0pionate. The reaction is exothermic, the tempera- ture rising to 8700. The reaction mixture was heated on the steam bath in sn.open flask for fifteen minutes. hater splits off readily, and it is advisable to allow it to escape. The mixture vss then heated gradually to 140°C. with the elimination of alcohol. It res found advisable to use an air condenser to let the alcohol out of the reaction flask and yet return the react- ants- Removal of the alcohol seems to increase the yield con- siderably and allows the temperature of the reaction mixture to rise more rapidly. Heating was continued until a sample of the oily mixture became solid on cooling. This required only about fifteen minutes or trentv minutes. The viscous mass was ground -29- with ether whereby it solidified to a white crystalline mass. There first crystals obtaines from the reaction mixture were small rhomboids with a melting point of llO-llZOCa These were vashad with a small amount of ether and allowed to dry. Yield: 37.4 gns. (91.7%) A number of condensations were carried out to determine the effect of temperature on yield, and the opttnmn temperature was found to lie between 100°C and 140°Cl * Condensations were made varying the proportions of the re- actants. tith a ratio of ester to hydrazine of 2:1, the yield is decreased to about 80%. moreover, with an excess of hydrazine there is a great increase in dark-colored oily decomposition pro- ducts rhich'make the purification of the pyrazolone much more difficult. ” The pyrazolone was purified by recrystallization from di- lute alcohol, and an interesting phenomenon.was observed. The entire yield on first crystallizing out of the reaction mixture was rhonboid crystals, which on repeated recrystallizations chang- ed to the monOclinic form. The proportion of monoclinic crys— tals constantly increased until finally the entire product had that crystal form.’ The melting point of these white needles was 112-11300. Taking a mixed melting point with the the crystalline forms, the melting point was depressed to lOO~104°C. The possibility that the two were isomeric forms of the pyrazolone was consid- ered, also the possibility of adsorbed impurities. It was also a possibility that the monoclinic crystals were a hydrated crystal. It was found however, that the change in form occured even with recrystallization gfrom absolute alcohol. The same phenomenon was observed using acetone as the solvent. -30- Foth crystal forms of the pyrazolonc were analyzed for the el- ements with the following results: 313H14N?0 ~ rhomboid d carbon hydrogen nitrosen Theareticel VITEE‘ 6293’ ICTEE Found 71.41 7.08 14.03 Gigglaflso - nonoclinic carbqn hydrosen nitroeen Theoretical VIIEE ’.96 .a Found 71.05 6.95 13.97 )Benzoyl esters were prepared from the two crystalline forms, and both were found to give one benzoyl derivative melt- ing at 70-71°C. .A mixed melting point using the benzoates pre- pared from the two forms showed no depression. it appears pos- sible th=t the forms may be isomers, or it may be they are simply polymorphic forms of the same compound. Neither possibility has been confirmed or discredited. The pyrazolone was found to be soluble in both alkali and mineral acids. It is soluble in alcohol, acetone, and chlor- oforn, and is difficulfly soluble in ether and eater. -31- IV. Preparation of l-O-Tolyl-Saathyl-é-methyl-5-Pyrezolone The o-tolyl-B-ethyl-éqmethyl-S-pyrazolone was prepared by the same method used by Emmerling and‘Kristeller, condensing o-tolyl hydrazine with ethyladtopropionyl propionate. The eq- uations below show the reactions in the formation of the pyra- zolnne: /// . _ 0 :0 (JHOH)* NH 5 c2356- was, 9 / ocsaa E" =0 c.2235 """’ 4H3 odTolyl Ethylok-propionyl o-Tolyl hydrezono of hydrazine propionete the ester 3 9115 (-cgesoE-n; _=0 ‘H l-o~Toly1—5-ethyl-’ 4dmethy1—5-pyrazolona Twentyufour grams (0.2 mole) of O-tolyl hydrazine wee ed- ded to 32 gas. (0.2 mole) of the ester. The reaction mixture splitting off rater is exothermic, the temgereture of the re- action mixture going to 94°C. where the mixture starts to boil. The reaction wee carried out on a steam bath for thirty min- utes and then heated to 150°C. over a thirty minute period. The mixture mes cooled somewhat, and the viseous mass was ground with ether and pyrerolone solidified to a white crystalline mes . -32- Here, as with the phenyl-5-ethyl-4dmethyl-S-pyrazolone, the first crystals were rhomboids. Their melting point was 148-14900. The yield was 35.§ gms. (83.1%) On recrystallizing from.dilute alcohol a number of times, the pyrazolone was gradually converted to monoclinic crystals, melting; point at 155-15600. The mixed melting; point of the two forms was 130-15400. Grinding the resinous mess of the reaction mixture with aasone and letting it stand also gave rise to rhonboids which after repeated recrystallizations were changed into vhite need- les melting et 135-15600. The gyrezolone res analyzed for the elements with the fol- lowing results: Carbon hydrogen nitrogen 1 Theoretical 72.3 7.41 12.96 Found 73.1 7.25 15.11 Many attempts were made to prepare the henzoyl ester of . _ _!_' __ ..__._._L' ~_ ‘— the pyrezolone with both of the two crystal forms, but without success. Both the regular Schotten-Bsumun and the modificstion using pyridine were used without being able to isolate the hen- zoyl derivative. The pyrezolone is soluble in alcohol, chloroform, and tol- uere. It is difficultly soluble in ether, ligroin, and pet- roleum ether. -33- V. Preparatien of 1-Phenyl-4- }.Iethyl-5Q thyl-S-Pyrazolone The l-phenyl4-methy1-5-ethyl-fi-pyraaolone was prepared according to the method given by Michaelis (37). Acetyl phenvl- hydrazide was condensed with ethyl-dk-propionyf propionate. The reactions involved in the condensation are shown in the equations: 0:52-84; - n ° + HO- g—c’ + P011 (-11. 1:) (g @2115 \OEt ‘5 Acetyl Phenylhydrazine Enol of EthleKpPropionyl Propionate -0585 n-c6q5 +301 (cc ) 0333-3 «3285 4235 2 283 + , N313 + ca; c” 02356 ~03, c «on, 3“:31 Lootyl phonyl hydrnzonc of 1’Ph3931“‘lfithl1'5‘0thil- ethyl prepionyl.pr0pionatc 3-pyracolono The acetyl phenylhydrazide was prepared in the following way: To 44 gas. (0.4 mole) of phenlhvdrazine 30 gas. ( 0.5 mole) of glacial acetic acid were added, and the mixture was refluxed for six hours. The reaction mixture vas poured into water, and the entire mas s \as ev‘porated to dry ass on the sttmim bath. ”he brown crystalline mass was dried on a porous plate, washed with ether and again dried on a porous plate. The product was recry- stallized from hot water, and when pure, had a melting point of 129-1: 50°C. The yield was 29. gms. or 49” of the theoretical. The acetvl phenvlhvdrczid‘ crystallizes in large colorless leaves. It is insoluble in alcohol, ether, and petroleum ether, and is soluble in hot water. The reaction is shown by the following eguation: -34- )1 H‘nnz + ca3coon ——=. “(lg—coca} Acetyl phenyl hydroxide ‘ (Hydracotin) The 3-pyrszolone was gre1ered bv Ll cin3 33 gas. (3.2 mole) of ethyl-dknpro pionyl I1rogion1te in a fL sic with a reflux con- denser. Through the reflux condenser 54 rue. (3.25 m 11s) of Izho 3ghorls tri chlori de vars zsdded slo.1v. The flask was he tef, and the mixture refluxed until no more Lei hVB evolved. The reaction mixture was poured with stirring into a 10; solution of hydrochloric acid. The solution was filtered and then nea- tralired 13th awmonimn hudroxide precipitating the 3—yyraaolone. The pyrzzolone was filtered off and was purified by recrrstel- liaition tron dilute alcohol. The [T0 mdlct 0 me dovn as small creon colored crystals neltir. at 97-9890. The yield tea 15 gas. (355) The S-vyrazolone is SOIJEIB in ether end nearly in- so11zcle in rater and Latrolean ether. A nitrogen delermination nus run on the fi-pyrnzolone. The results obtained were: C l 3"}? 1 1‘7” r' ‘3 r11 t. re sen Theoretical 13.9; 14.1 Found -35- VI. Preparation of tb o BUI.wZOY1 star of l—Ihonvl-Lo 3'l~&— IXBthyl-S-Pyrozolonc. The bon2031 ester of the yyrnzolone was preparcd by c meth- od 3513118 qr to th.:: t used by: Michael 9 (3C). A w‘ixtmc of5 051313 of pyrazolonc, 10 gas. of pyridine, and 5 gnn. of henzoyl chlorlfle was shaken together in o stopyur- ea . ml. orloznyor flask and alloxcd to st: nd for t1 Tty-foxr hours. The contents were roared into water and washed voll with water, tfiec with dilute sulfuric acid, (5;) then vith a dilute solution of sodium carbonate (5E), and finally vcahed again with motor. The yroduct was purified bv rccrrstelliz:tion from di- Lite alconol and ca1o dotn 93 f3 1c white necafiLlos molt n5 5 73-7100. Yield: 4 ans. (535) -C5H5 -c535 Pzridinoi * a + CGHSGOCI “0635 The foruula shovn is in accord V1tn :norr's formula for tie tenzovl or tirs in which the benzovl regions is attache d to tho 0 rboryl groqy. T‘he l-phoryl-Zfi-etb Vl-d-uot1vl-c-ton7031 -pyrszolono is soluble in alcohol, chlsxroform, and in hot soline ané liot lingroin; slightly soluble in carton tetrachloride and insol- ublc ifl got or cringetrolcun other. A nitrogan eletor inntion wr1s r1zn on ti1e ton zovl ester: Clé‘iil‘fi'tO’ nitrovon *eflreticol ..14. Found 8.98 -35- The 3,5-d1nitro benzoyl ester of the pyrazolone was pre- pared by condensing 3,5-din1tro benzoyl chloride with l-phenyl 3-ethyl-4—methy1-5-pyrszolone in pyridine solution. The pro- duct was handled as described above and was purified by recry- stsllizstion from dilute alcohol. The 3,5—din1tro-benzoate came down as creem~colored needles melting at 91-9200. -37- VIII. Hethyletion of I-o-Tolyl—B-ethJI-e-eethyl-S-nyexenone The pyreeolone wee methylated ueing the method employed by hnorr in the preparation of tolyl entipyrino. (29). Ten grene of the pyrezolone were heated in e eeeled Carine tube with 10 gnu. of methyl iodide end 10 ans. of methyl elec- ho]. for six houre et 110° 0. The methyl alcohol wee noun-a off under reduced preeeure and the hydroiodide dieeolred.in eater. The nethylated.product wee liberated by the eddition of radium hydroxide (3? gen. per 100 ll. of aqueous eolution). the product eee extrected either with chloroform or with ether and dried over enhydroue calciunioxide. The product nee purified by dieeolving in hot geeolinc end letting etend in the ice cheet. The product cane doen ee_e vieccne oil ehieh cen be cryetellieed in the ice cheet but which quuifiee et rooe temperature. The eeee oily product wee obteined tron three eethyletione ehich were run. Attempte to obtain e cryetelline product using e nun- ber of different eoivente (eater, ligroin. geeoline end chloroform, and geeoiine end eleohoi) were uneucceeefol. The product 1e evidently en oil. -38- YIII. summary A etudy wee node of the oondeneetion of the phenyl end o-tolyl_hydreeinee with ethyldiapropionyl propionate to give the beryl-34th:lot-nethyl-S-pyreeolonee. The l-phenyl-B-ethyl-d-Iethyl-pyreeolone wee prepared end wee found to come down we rho-bold cryetele melting et 110-1129 C. The rhonboide on repeeted recryatellieetione were changed to eonoelinic eryetele with e eelting point of lie-113° 0. (Yield 92%). The lye-to111-3aethyl~4-eeth:l-S-pyreeolone wee prepered end it too ceee down et firet ee rhonboid eryetele. H.P. 1&8- l§§° c. After recryetellieetion theee were chenged into nono- elinic oryetele eeltina et 155.1560 0. (Iield 83%). In.both of the ebowe eeeee e nixed melting point of the two cryetel force wee found to ehow e depreeeion of ebout 16°C. Acetyl phenyl hydreeide (hydrecetin) wee condeneed.with ethyldiepropicnyl.propionete to give lpphenyl-toeethyl-S-ethyl- 3-pyrezolone which cene down ee fine creee-colored cryetele with e melting point 97-980 0. (Yield 35%). The benzoyl eeter of l-phonyl-Boethyl-e-nethyl-S-pyreeo- lone wee propered ee wee obteined ee fine white needle: melt- in; et 70-710 C. (Yield 53%}. The dinitro- (3.5-) benzoete wee also prepared. The cryotale came down an credencolored needles with e melting point of 91-929 c. Attempts to prepare the heneoyl ester of l-o-tolyl-Buethyl- 4-nethyl-5-pyrezolone were uneucceeeful. The o-tclyl-B-ethylye-nethylps-pyreeolone wee nethgleted end the product cane down ee e wiecoue oil. Attempte to ohtein the methylated product in e cryetelline fore at room tempere- ture were uneucceeeful. The l-o-tolyl-2,4odinethyl«3-ethyl- 5-pyreeolone ‘ie epperently en oil et ordinary temperaturee. 12. 13. 1‘. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. -40- B 13 1.108%“) HY Knorr, Ann. age, 137 (1887}. Knorr, Ann. & , 188 (1895}. Knorr, Inn. 221. 1 (1396). Knurr, Ann. 13g, 6? (1903). Knorr, Ber. ah, 715 (1335). Cloieen and Reason, Ber. 31, 1333 (1890). Cleieen, Ann. ZZQ. 251, 267 (1898). Bucnnor end Fritech, Ann. 211, 253 (1393). Eelhiano. Ber. 21. 1103 (1890). China, Ber. 1Q. 3656 (1903). Khorr, Ber. lg, 2597 (1333). Knox-r. Ber. $1, 149 (1883). Knorr, Ann. 223.. 151 (1887). Knorr, Ber. __1§_. 311 (1884). Buchner. Ann. 311. 21% (1893). Biechlcr, Ber. a, 31‘} (1892). Biechler, Ber. 2Q, 1831 (1893}. Fischer and Bulow. Ber. l§. 2131 (1884). Stoermer end Rertineen, Jinn. :53. 322 (1907}. Schmidt, 9:59.932 W. ssh-557. Knorr, Ann. 29.1. 58 (1396). Fischer, gfifi, 116 (1836). Cornelius end Hoeolke, Ber. lg. 2239 (1836). Brighem.wlfldw Deriwetiveeiijreeologe (1929). Sell. £9.29, Elli}. ism; W (1931). KnOrr and Klote. Ber. 22. 2545 (139?). finorr end Duden, Ber. 25.. 761 (1892). -41.. 28. Stole, Ber. fl. 3275 (1905). 29. Knorr, Ber. 11. 550 (1884). 30. Ileuher, Honeteh. ll. 28}; 12. 215 (1890, 1891). 31. Bleiee, Conpt. rend. m, 979 (1901). 32. Knorr and Blank, Ber. 11, 2050 (188‘). 53. Knorr, Ann. 215;, 162 (1887). .35. * Ennerling end Krieteller, Ber. 32, 2452 (1906). 36. Schroeter, Ber. 22. 2719 (1916). 37. licheelie, Ann. m. 273 (1905). 33. Hichaelie end Bohr-one, Ann. m. 310 (1905). 39. Stole, Ber. 21. £07 (1894). 40. Fichter, Enzeneuer, end Uellenherrg. Ber. 11, #98 (1900). 41. Michaelie and Drewe. Ann. 152. 321 (1906). 1:2. lief. Ann. agg, 125 (1892). A}. Knorr, Ann. m, 202 (188?). #8. lcElwein, J. Lu. Chen. Soc. 11,. 3129 (1929). #5. Deeonbreun and Ire-ere. J. All. there. Aeeoc. .13. 589 (19230. 86. Peldheue, Ann. m. 73 (1863). lllllllllllllllllllllllli 7 8511 I] 1 3 0 3 9 2 1 3 l I