[1950] Avison and Morrison: Synthetic Analgesics. Part VI. 1469 303. Synthetic Analgesics. Part VI. The Synthesis of Ketobemidone. By A. W, D, Avison and A. L. Monson. ‘Ketobemidone (Hoechst 10720) has been prepared from m-methoxybenzyl cyanide by condensing it with methyldi-(2-chloroethyl}amine in the presence of sodamide, submitting the resulting eyanopiperidine derivative to a Grignard reaction, and demethylating the product ‘with hydrobromic acid. ‘Tue analgesic drug, 4-m-hydroxyphenyl-1-methyl-4-piperidyl ethyl ketone (VI; R= H), was reported to have been made by Eisleb and his colleagues in the laboratories of the 1G. Farbenindustrie at Hoechst during the war (U.S.A. Office of the Publications Board, Department of Commerce, Report No. PB-981). Under the name ketobemidone (Hoechst ‘No. 10720) it has received pharmacological and clinical investigation (Kirchoff, Fed. Proc., 1948, 7, 234; Lewis, J. Pharm. Exp. Ther., 1949, 98, 410; see also J. Amer. Med. Assoc., 1948, 188, 975), being ‘about ten times as active as pethidine. No details of the synthesis or physical properties of the compound were available at the time of carrying out this work. However, very recently Kagi and Miescher (Helv. Chim. Acta., 1949, 82, 2489), who refer to 897,453, which we have been unable to consult, described its preparation by first condensing 3-di- methylamino-1-(m-methoxyphenyl)propyl cyanide and 1-chloro-2-bromoethane in the presence ‘of sodamide to give 4-cyano-4-(m-methoxyphenyl}-I : 1-dimethylpiperidinium chloride. This salt was then treated with ethylmagnesium bromide, and methyl chloride removed from the resulting ketone by the action of heat. Demethylation gave (VI; R = H) which the Swiss workers call “ Cliradon.” crime AA AHEM —__ A LE-CENOHCOM CY" 8s = OY = { = NZ wh a0 C c ‘Vite ine a) ql) (IL) He \ Hy a No we ot a H HyCN ASK oN SX ee > 6 i, sth im er mn Nef, We decided to prepare the ketone by a Grignard reaction on the nitrile (V), which Kagi and Miescher obtained by the action of heat on its methochloride, with suitable protection for the phenolic hydroxyl group. ‘To prepare m-methoxybenzyl cyanide (Chakravati and Rao, J., 1938, 172), necessary for the preparation of (V), we used the rhodanine method starting from m-methoxybenzaldehyde (cf. Julian and Sturgis, J. Amer. Chem. Soc., 1935, 57, 1126). This gave m-methoxybenzylidene- rhodanine (I) and thence m-methoxyphenyl-e-thiopyruvic acid (II) and the oximino-acid (III).1470 Avison and Morrison : Synthetic Analgesics. Part VI. ‘This was not easily isolated in good yield, but the crude product with acetic anhydride underwent dehydration and decarboxylation to give the required m-methoxybenzyl cyanide (IV; R = Me) in 52% overall yield from the aldehyde, ‘Treatment of (IV; R = Me) according to Washington Report PB-981, p. 85, with methyldi- (2-chloroethy!)amine resulted in 4-cyano-4-(m-methoxyphenyl)-1-methylpiperidine (V; R = Me). Ethylmagnesium iodide converted this into the ethyl ketone (VI; R = Me) which was readily demethylated with aqueous hydrobromic acid to ketobemidone (VI; R = H). EXPERIMENTAL, m-Nilpobencaldehyde —When a mixture of potassium nitrate and concentrated sulphuric acid was used in he titaton of teneldchyde second fo Ehich (Br. 168, 16, 2010 te eaten tare adel to set to a hard: honey like Cosastoucy an early rage’ thus prowating wring ans meee imnponibie to work with more thana fow prams ata tine.” the tllowing method wes feed attastogy = Soncentrated sulphuric acid (660 snl) was tented sith Concentrated me aed (Auslate 600 a) with cooing. Usea'(-0 g) ws aded aad the wel-sisted satire cooled 16 057 ure benzaetds {300} wasinow added at sucha rateas fo keep the temperature of che reaction mixture between 0” ad G1? Glcr tne addition sya complete sting bas contiseed at € for Ij hours, te mieeure was thes added to crushed ite (ca Sg.) and te pale yellow sok whieh separate tivered and washed taooughly with water and finaly vith ght petoleua (bp, 40-809. The yet of crude m-nitphoneldehds Tier drying was 8096 G10 g)" Alsinglereerytaisation fom ether light petioloum sulle to purty the compotad,” it'had mop. 81-86" and’ was ideatieal wih the Satral prepared aceoslbg © Hhnith: "Wor large quantities the crystallation was bent cariea out wate aqudoss acetic se in llethouybendaldchydeccthe mebivobenealdchyde was reduce! in"100¢ batches bye method described in Org: Spmth (25, 68) and converted tate mtydronjbeasaldeide ia yields waich were Ssualy below 4056.” "Tho ater as methylated according 2 Lapverth and Shceamite U7, 1028 1580, my hhoujbsdenehoanine hem Metgybengsigdy ae (td §) and dani 3 ¢] were aiaaved in Hot glacial scete aed (260 i) and powdered anySrous Sodium acetate 150 g added, ‘The mixture was boiled renty under retuy with Shaking for 0 minstes. "The reaction miscore sees poured into cold water 2) au the yellow old product 8 9200) wolated by fitation aad Wesbiag THE ater, lcehol and Analy with ether, The compound cbiatael thus was preclesiiy pare, having Tin, pol 2912805, the abalytieal specimen cryeaticen tom nitobensead i yoy atte a $ab-Bad" Pound's ¢, 026: 1h Sd; NOT. Cyclo NS roquses G20, HE 2:0, N55) rm-ifehonyphonyiccthiopyraie anie (i). above thodnine dotivative (30) was heed with asspaqucons eum hyorecite (17 my o the waterbath eal i nad danlved shen fra fare Ie"idnttee, Cooling in an lesak mixture and rapid addon of 10% kydrocuorie aud (LT al} Caused he Separatiog of the aeid'asa dark slwhick wolidined when rubbed Yo eyclow sold (17-3 np. D0 dll eer stallsation fom syloyenane ralael the trp. W 86--08" (Souad CTO, PoP Sak Ogtigssenqurn Cot, Hy kas S Toa tents uot 4) a Orimino-p lt Redo henshproploic etd (11) Weicoxylamine hydrochloride (10-5 g) in water (10'ml) waa added ia solution/of sodium (95 6) im absolute alcohol (GO mi). After omoval of Bie aul ahlonds by Alraton, the solution wae Added 00 w-mcthorspbenyt-ethlopyravic acid (ioe g) and the mixture bolled oF S hours. “Conces\ation i oueue’ fave a Sem Sgld teslue {to SaBoagucnt work this wes sed duecty for conver into the mitsieh which as Saslved i Hastsoaid hydroxide, Acdigeaton of tis ssletion precipitated the ovime as a gum which partly cystalied wien rubbed and covled,"Ktherrextraction Sf te semraolid (eaving soe sticky sternal edbwolwan) and concentration af the extract puve's gum hich solitsed andes Donsene: Te wits Solid (5g had mp, 19-“1d0" (decomp). Rectystlistion from bonsene raised the'm pt 190 i0" leediip) troubi 6, 578; WELT? N, 12. Cult OA cequices Oras He OF, W O10, im dathobjbinst Cyanide (A; I Ste Owing'to the aneabalucory yield of pare oxime (the reihod eserbed was pelea to use the erade eoucentrated teachin iaxture ebm hyaronpline od ike thiorcld (18 gh. “Acetic salute (200 mi) was addled with ieeveling at ant co moderate ie vigorous reaction, did Analy the mixture was wormed on tie waterbath ail eburvescence bad teased. Concentrating tie vesting soletion de soca, Gisolving the reduc iw ethers waskigg tt dlivte sodium carbonate, drying, ai aislling gave the equred wrancthouybensyl cyanide GOS 6) asa pale yelow of bp. Las 1a mm, (hosnd : N, 836, Cale for HON, W954) ‘esslanenyptonil i mais ppeayi Biot Keone (Vt; = Mel -cyane-ontaethony. phenji-Lavetapipeedine (7 g) was abed ¢2 the Grigaaed reagent trom magnesium (25 8) aad EiTinde (186) the eer Sed in ti preparaon had been fepacel by dy benzene (8) Ry mixtaro was Deuces nlsing tor 18 Hours aod then Coated and ddcomposed wi ice and ammonium chloride solution, “The eeulting benzene solution of the intermediate, Ketimine. was invdrolysed by heating it with 2v-hydrochloric acid. After the aqueous layer had been separated and smade strongly alkaline the required Ketone was precipitated an extracted with ether. Distillation fave a practically colowriess oll (26 g), bp 190—-fa4 0-9 mm. Found: N, 08. Cale for Call yON + Ni's-4&).. Kasi and Micscher give b, p. 126-1260 /0-02 mm, mp. 5358 ‘(eeityarosyphenyl)-L-methyi-tpiperidyt Ethyl Ketone (Retobomidone) (VL: Ro» H).—The methyl ether (2.5 ) wan Gemethylated by boiling it with 48% aqueous hydrobromic acid (20 mil) for 1 Rou. ‘The dari solution was concentrated sm vacuo and the residue dissolved in absolute alcohol. On addition of an equal volume of dry ether to the hot solution and cooling, the hydrobromice (24g) of the required Rydroxyphenylpiperidine slervative separated ia. light-brown crystals, m, p- 191-192". Ropeated crystalltation from alcohol-ether (chartoal) increased the mp. to 199-—18a* (agi and Micacher found mp. 19¢--190°) but did not removeall the colour (Found : Cr 442 17,64, N45; Bre, 24. Calc fort Hg O.NBr! C548; 1, 67; N43; Bre, 244%)[1950] Avison and Morrison: Synthetic Analgesics. Part VII. 1471 ‘This compound was obtained equally well by boiling the crude Ketimine from the Grignard reaction with 48% aqueous hydrobromic acid. ‘The hydrobromide (8-05 g.) was dissolved in water (15 mi) and Brcaumnla (20 ml} added to precipitate the free bac, a practically white aod (2° gm. p. sd AG1" (Kagl and Micacher give ap. 166—166°) (Found: Ny 6-65. ‘Calc. for Crdlle,OaN 2 N, 5:7%), Ketobomidone hydroehoride was Eade by the action of etreal hydrogen chlotie of the Bane, “It had m. p. 196-107" (Found : C, 68-4; H, 7-6; N, 49; Cir, 12-5,” Cale, for CyyHq40,NC1: C, 68:5; H, 78; 58,49; Ci-, 12-5%). agi and Miescher reported ei90", Raszancn Derarruent, Rocue PRopvcrs Lunrep, WELWYN GARDEN City, HERTS. (Received, February 16th, 1950.] pit