Journal of Medicinal Chemistry, 1971, Vol. 14, S o . 9 891
NOTES
TABLE I : SUBSTITUTED ETHYLENEDIAMINES IV
% , NO.
N\&.!
B p (mm) or m p of base, OC
M p of hydrochloride, OC
Crystn solvent
N-Piperidino 193-195 (4-6) 278-279 A' N-Morpholino 220-222 (10-12) 285-286 A N-Pyrrolidino 173-175 (4-6) 295-296 B N-1,2,3,4-Tetrahydroisoquinolino 248-250 (8-10) 265-267 A 5 4-Benzyl-1-piperazino 253-255 (4-6) 261-262 A 6 4-p-Chlorophenyl-1-piperazino 97 264-265 B 7 4-Phenylpiperazino U 264-266 A 8 4-rn-Chlorophenyl-1-piperazino 263-265 (4-6) 266-268 A 9 i-PrpN 184-187 (4-6) 232-235 C a Decompd during distn. All HCl salts were analyzed for C , H , N, C1, and the values. c A , MeOH; B, E t O H ; C, EtOH-Et?O. 1 2 3 4
dures.18 I n these, 1,Fpiperazinedicarboxylic acid Et ester is invariably formed d o n g with 1-piperazinecarboxylic acid E t ester. Further the methods are tedious and work-up is difficult. I n the present procedure, formation of the disubstituted product has been totally avoided. 1-Piperazinecarhoxaldehyde19 is first converted to 4-formyl-1-piperazinecarboxylic acid E t ester20 which on hydrolysis with NaOH (10%) for 4 hr gave l-piperazinecarboxylic acid E t ester in 85-90yG yield. Substituted Ethylenediamines1V.-A mixt of 4-(p-chloroethyl)1-piperazinecarboxylicacid Et ester. HCl(O.05 mole), the appropriate secondary amine (0.05 mole), anhyd KzCOI(0.05 mole), and abs EtOH (50ml) was refluxed for about 6 hr, and the solvent was removed by distn. The residual material was treated with H20 and the a y soln after basification with 50% KaOH soln to pH 9 was extd with Et20 The ext was dried (Na2S0,) and coned to afford the desired product as liq which was distd i n vacuo. I n all cases the viscous liquids finally obtd were converted into the corresponding hydrochlorides by passing dry HCl through an Et20 soln. All compds were characterized as their hydrochlorides. Only 6 (see Table I ) gave an anal. pure sample of the base on crystn from petr ether (bp 60-80"). The characteristics of I V have been recorded in Table I.
Acknowledgment.-The authors wish to thank the Council of Scientific and Industrial Research, New Delhi, for the award of a research grant' to carry out this investigation. Thanks are also due to the authorities of the Bengal Immunity Research Institute, Calcutta17, where the major portion of the work was carried out. (18) (a) T. 8.Moore, M . Boyle, V. M . Thorn, J . Chem. Soc., 89, (1929): (b) H . K . Hall, Jr., J . Amer. Chem. Soc., 78, 2570 (1956); (c) K. R . Jacobi, Ber., B66, 113 (1933). (19) K. Fujii, K. Tomino, and H. Watanabe, Yakagaku Zasshi, 74, 1049 (1954). (20) (a) W. Logemann, D. Artini, and G . Tosolini, Chem. Ber., 91, 2566 (1958) ; (b) conversion of 1-piperazinecarboxaldehyde t o 4-formyl-1-piperazinecarboxalic acid E t ester is more advantageous t h a n t o convert l-piperazinecarboxalic acid E t ester t o 4-formyl-I-piperazinecarboxalic acid E t ester according t o t h e method of Logemann, et al.208
Optical Isomers of Mepivacaine and Bupivacaine BENJAMIN F. TULLAR Sterling- Winthrop Research Institute, Rensselaer, New York 12144 Received March 2, 1971
Current interest in the potent local anesthetics mepivacaine and bupivacaine-N-methyl and N-butyl derivatives of ( f)-2',6'-pipecoloxylidide-(I) prompted us to prepare and study the optical isomers. The parent (* )-I was resolved using dibenzoyl (+)-tartaric acid. Mepivacaine was resolved by crystallization of
Formulab
-Pressure Dose, mg/kg
response, mm--. Fall
Rise
C,,Hz,N302.2HCl 25 Nil Kil C13HzjN303.2HCl 25 Si1 Nil C13H?;N30?.2HCl Ct8H2,N302.2HC1 10 62 Nil CzoH,zN,O,.2HCl 25 41 Nil C19H29ClK,02~ZHC1 25 Biphasic C10H3oX402.2HCl 25 Nil Nil -_ Xi1 C1gH29ClN402.2HCl 10 ai) CijH31N,On.2HCl 25 Nil Nil anal. results were within +0.47, of the theoretical
its quinic acid salts.' Although a number of optically active acids were tried as resolving agents for (+)bupivacaine, no separation of the isomers could be effected until seed crystals were made available by Sbutylation of (-)-I and crystallization of its salt with (+)-tartaric acid. An observation that (+)-mepivacaine . HC1 and (-)-bupivacaine . HC1 were significantly longer acting than their enantiomers has been reported in an earlier publication from this laboratory.2 Thus it became of interest to establish their configuration. This was accomplished by preparing from ( R ) - (+)-methyl pipecolate3 and 2,B-xplidinomagnesium bromide4 the parent (R)-(-)-I identical lvith (-)-I by resolution of (*)-I. S-Butylation of a sample of this (@-I gave (8)-( +)-bupivacaine and S-methylation of (S)-I (obtained from resolution of (+)-I) gave (A)-(+)mepivacaine. Thus, the longer-acting (+)-mepivacaine and (-)-bupivacaine isomers are both of the ( S )configuration. Experimental Section Resolution of 2',6'-Pipecoloxylidide (I).-To a soln of 42.0 g (0.15 mole) of (&)-I iii 300 ml of boiling i-PrOH was added a soln of 38.0 g (0.10 mole) of dibenzoyl (+)-tartaric acid monohydrate (DBT) in 300 ml of boiling i-PrOH. Immediate crystn occurred which was completed by slow stirring while the mixt cooled to 39". The ppt was collected, washed with i-PrOH, mid dried a t 70" to give 32 g of (+)-base IIBT salt, nip 186-189". This crop was converted to base by suspending in 300 ml each of The Gt?O layer HzO and Et20 and adding 8 ml of 28% ",OH. was sepd, washed with H 2 0 , and coned in vacuo. The residue was crystd from boiling hexane to give a 12.0-g first crop of the D (c 2.3, 1 ATHCI). This robbase, mp 130-132", [ c u ] ~ ~+46.1" tion was unchanged after recrystn from i-PrOAc. The resoln liquor was evapd in vacuo, and the residual crude ( - )-base DBT salt was converted to base as above and recrystd twice from boiling hexane to give 11.1 g of base, nip 130-132", [cY]~'D -46.8' (c2.3, 1 j\:I%C1), [ a I z 5 D -11.04 (c5, LIeOH). Resolution of (+)-Mepivacaine.--il sohi of 46.0 g (0.186 mole) of (f)-mepivacaine (mp 149-151') with 38.4 g (0.2 mole) of quinic acid (Freas Bros.) and 400 ml of abs EtOH was seeded a t 60" and stirred and cooled to 25'. The cryst ppt was collected and recrystd from 300 ml of 95yc RtOII to give 34 g of (+)-base quinate, mp 192-195'. This salt was dissolved in 300 nil of H 2 0 and basified slowly with ",OH while rubbing and stirring to induce crystn. The pptd base was collected, washed with H 2 0 , (1) B. T . Ekenstam, l3. von Egner, and G . Petterson, Acta Chem. Scand., 11, 1183 (1957), mho resolved mepivacaine "with t h e aid of tartaric acid"
b u t gave no details. ( 2 ) F. P. Luduena, Annu. Rev. Pharmacal., 9 , 503 (1969). (3) P. S. Portoghese, T. L. Pazdernik, W. L. Kulrn, G. Hite, and A . Shafi'ee, J . M e d . Chem., 11, 12 (1968). (4) Thuresson and Egner, U. S. Patent 2,799,679, These authors used t h e Bodraux reaction t o prepare several racemic 2.6-xylidides.
892 Journal of .Iltdzcinal Chemistry, 1971, 1-01, 14, S o . D :ind dried at 70' to give 19.0 g of nearly pure base. A 1-g portion rerqrstd from i-PrOAc melted :it 15S-155', [ C Y ] % -63" ( c 5, AleOIT). A 10-g sample of the ba5e wah di>solved i n 100 ml of i-l'rOII and neutralized by addn of 3.9 ml of concd HC1. The niixt wis cooled t o :io and filtered to give, after drying, 8.0 g of :+l-h:i>e.I-ICl, mp 29:3-29.i", iCYIz2u + l ! j o IC 0.5, H,O). Anal. &lK,O) c1. ,ipn of the remlii liquor arid conversioii of the residue to the :is above yielded 2.5 g of the crude enantiomer. This mater i d was treated with 17 g of (+)-tartaric acid i n 400 m1 of 95'; I.:tOH, : i d the soln wa5 kept several h 2.5". X total of 30 g of d t , mp 83-83", was isolated? and re tn from 30 nil of H?O :it T,' gave 25 g of piire !+)-bitartrate, 100-101". This salt \vas converted t o base a'; above (12.7 g ) which by rieutralixation w i t h roiicd HCI i n i-PrOH gave 12.0 g of f - )-base.HCl, m p %9:i-2!),-)', [a12'U - 18.6" ( C 5 , H?O). Anal. (C,-,€T,,CIS20)C1. A . ~ m p i of c the t):ise prepd from this salt melted a t Ilit3-15.i0, / ( Y ~ ? ~ I+6:;" J I C -5, AIeOH). Resolution of ( +)-Bupivacaine.-.% iolii of 41%g (1.42 moles) .44moles) of (+)-tartaric of (-i)-biipivacaiiie bake aiid 216 :ic>itl i n 1500 ml of boiling i-I'rOH ,ceded arid kept at 3" for 2 hr. Fvith orc.asional hwirling. The y ppt was filtered, washed with i-I'i,OII, :iiid dried to yield 200 g of nearly pure (+)-base i )-l:ir!rnte, m p 18:3-184", iirichariged by recryytii from i-PrOH. ronverted to base (dil ",OH, -rude ( 't-ba,e, nip 128'. Ree 6.*i g pure i + )-ha?e, nip 13.5-
+
+
1 of hot i-PrOH and neutralized the add11 of 2,:J nil of w n c d IICl. After evapii in mcuo the , t d f r o m 30 ml of i-1'rOH to give 6.0 g of ( +)2.iS3, [ C Y ] ~ ~ +~ 1) % . i 0 i c 2: I130). A m i . (CISlIL,C"O) c1, s. The i.e.0111 liquor oil +landing at 25' with orca&nal ieratchiiig :iiid >wii,liiiggave after .i k 00 g of rrude ( - )-bupivacaine (+)fi,artioiiwa,y tli.~wlvedin 2 1. of H20 t:iI,trnte, nip 110-1l.iO. 'I SFI,OH, t o ppt 2.50 g of ( - )-rich ( J f i-I'iOII gave 120 g, nip 132-134", 00 mi of i-I'rOH t o yield 109 g of pure CY]^)*^ -8(J,DI.R,*BRI I N €1. BUTCHLR, U \ Y I D ,4 BUXTON, I U D 11 IVID J. H o v I L L ~ Chemical Defence Establzshment, Porton Down, Salzsbziry, TYzltshire, England ReceiLed X a r c h 12. 1971
Tyrosine hydroxylase is an important enzyme for control of catecholamine levels in vivo,since its catalysis of the conversion of L-tyrosine to L-dopa is the ratedetermining step in catecholamine biosynthesis.' The most potent inhibitors of this enzyme are the a-;\Ie aromatic amino acids,2-4 particularly close structural relatives of the natural substrate, such as 3-iodo-amethyltyrosine (I). We have synthesized a series of '2-aminoindan-2-carboxylicacids (11), in xhich the cr-lIe group is incorporated into the indan ring, in an attempt to define the active site of tyrosine hydroxylase. Sitratiorij of the spirohydantoin I11 derived from indnn-2-one. followed by catalytic reduction, gave the key intermediate, spiro (5-aminoindan)-2,5'-hydantoin (IV). Diazotization allowed introduction of a variety of 3 substituents, and the resulting hydantoins V were decomposed to the desired amino acids by the use of either concd HCl in a sealed tube at 160" or refluxing aq Ba(0H)Z.
I
+
I .
+
+
N
T
V 1. "03 2. H,, Pd/C
I11
In behavioral tests in rats, none of t,he compds in Table I affected spontaneous motor activity6 or conditioned avoidance responses,' suggedng an absence of (1) F Udenfriend, Pharmacol. Rev., 18, 43 (1966). (2) T. Nagatsu, M . Levitt, and 9. Udenfriend, J . B i d . Chem., 239, 2910 (1964); Anal. Biochem., 9 , 122 (1984). (3) W. S. Saari, J. Williams, S, F. Britbher, D. E. Wolf, and F. A . Kuehl, J . M e d . Chem., 10, 1008 (1967); R. E. Counsell, P. Desai. T. D. Smith, P. 9. Chan, P. A . Weinhold, V. A. Rethy, and D. Burke,,ibid., 1 3 , 1040 (1970). (4) S. Udenfriend, P. Zaltzman-Nirenberg, and T. Nagatsu, Biochem. Pha7macol., 14, 837 (1965); E. G . McGeer and P. L. McGeer, Can. J . Biochem., 45, 115 (1967); A. N . Lutsky and N . Zenker, J . M e d . Chem., 11, 1241 (1968). (5) .i. B. Mauger anti W, C . J. R o s s , Biochem. Pharmacol., 11, 847 (1962). ( 8 ) P . B. Dews, Brit. J . Pharmacol., 8 , 46 (1953). (7) R . W. Arimhlecombe, in "Modern Trends in Toxicology," E. Boyland and R. Goulding, Ed., Butterworths, London, 1968, pp 149-174.
