1052 Journal of Medicinal Chemistry, 1971, Vol. 14, S o . 11
Synthesis of 1-Methyl-1-(substituted benzy1)hydrazines DONALD E. BGTLER,* Susiix 11. ALEXAKDER, JOHSItT.AIC1JEAK,
ANI) l,IXDA\
u. STIi.kh'I)
Chemistiy Department, Jlcdzcal and Scteniific Affairs Dzvzsion, I'arkc, Davis and Coritpaui/, Ann Arbor, Xzchzgan 48106
Receaced February 18, 1971
h series of 1-methyl-l-(subst,ituted benzy1)hydrazines was prepared. A superior method for the prepai~itimiof 1-methyl-1-(ortho-substituted benzy1)hydrazines con$i>lsof the reaction of a n orthi,-xtib.tit~ited benzyl hnlitic, with methylhydrazine. Some of the aryl-substituted compourld~possessed lL40 illhihitory ac.tivit!- con~p:ir:tl)le to iproniazide.
I n connection with other synthetic studies underway in this lab, we required a large variety of l-methyl-l(substituted benzy1)hydrazines in quantities of several moles. A number of the products were tested for monoamine oxidase (JIAO) inhibitory activity. Methods for the synthesis of substituted hydrazines have been reviewed. l s 2 R e undertook the investigation of the 3 routes shown in Scheme I for the particular hydrazines desired. SCHEME I
+
\
CH NHNH
f IIIY-''
' B C O X Z
+
CH3NHNH2
nioles.14 On a scale larger tlxrri this, Ihr 1)repii is cumbersome niid the ~\-ork-uptedious. It l i : ~alw been noted that t h e rcactioii is characterized ti\. :I long iriductioii period follon-ecl h\- :I r~ttlicrviolent initial reactioli.l"lG TT-e recommend t Iiai 1 niolc of' the nitrosoamine bc added to :I gently refluxing. rtiiwtl, EtzO suspension o f 2 mole;-: of I,-IH :mtl t1i:it t l t c € I 2 evolution be monitored with :I dry g ~ i siiieter.Ii T h c H, evolution is due t o the lability of the first 2 I1 tr:ilisferred in tlie redn. Tliis is :dso tlie reasoii I: 2 : l i x t i o of 1,XH t o nitrosoamine il- riecewiry for high j.it>ld;-:. Grider these conditions no :ippreciable 1:iterit pried has been obsd. W e investigated t h e second i ~ t becausc c of tlic follov-ing facts: ( I ) :r large number of i n v e ~ t i g n t o ~ ~ s have all (in l u g e i ~ c c . s i j and obtained :rppreciable !.iclds of mono:illcyl lij,(lr~izines;"-s (2) at le:i*t one group had 1)reparcd hcitx\~lhydrazine (61%) :ind l.l-dibenz!~lhydr:izi~i~~ ) :\ (3) the commercial av:&ibiIity of meth\.lli~.tl~:izi~it.. A benzyl lialide ivitli :in ortho substituent I~irgcr than 1' or H gives high >,ields of tlir desired 1)rotluc.t when treated \!,it11 3--4 ccjuiv of met hylliyctrazi~io i n nnhyd EtOH (or THE') wln. 111 contr:ist, iho uiihindered benzyl chloride. w-cliloro-o-fluolotoluclic, :tiid '-(chloromethyl)p\.ridirir. g:i~i' iione of t l i p clesiretl product due to t h e form:ition of tlic 1 ,l,l-trisubl-titiit(.tl liydraziniuni chloridc. The p r e ~ e i i c cof :iddnl :iiuinulic: substitution did not itit(>rf(>w nit11 thc rt1:ici ion. Sonic. of the ortho substituents ~i,iediticlude: C1,131.. CH:,. OCH,, SCH,. Routc I1 i i t lrrl method ot' clioiecb for l-meth\.l-l-(ortl~o-s~ib~tituted beriz~-l)li!tli,:~zilit.; from the standpoints of co~ivciiieiicr. c:ihi'. t i i i i o wquired, safet and 'c:ile. Tlie oiily limit O I I l-c:ilcl is t h e size of the nwilablc :ipp. See Table I for t1:rt:i. The third routc can be iiietl o i l t h i . s:imr> walC :is t,he I+IH redti in m u t t I :uid i;-: convoiiieiit \vlicw tlie aryl acid, anhydride. or a r o ~ . lc h l o d e are coninicrci:il. Smith and co~vorl;ersl~~ 1iax.c prcpd benzoic :icitl 1niethylhydrazide from HzOH :iiicl i ~ i e t l i y l l i ~ t l r u ziii i~ i ~ ~ the presence of DCI : Hirini:iri m d l~'ulto11~ l ~ v prc~1)ci c tme using t h e xiliydrides and u-e htive used :iro~.l halides. Hirimanlz has prepd l-beriz>-l-1-n?cIliylh!.drazirie (1) ill 55:;- yicld from pure bcuzuic :rcicl 1>.3
If the K-SIe-substituted benzylamine is commercially available, route I, the IAH redn of the N-nitrosoamine,13 is a useful lab sequence up to a scale of 1.5 (1) P. A . 9. Smith in "The Chemistry of Open-Chain Organic Nitrogen Compounds," Vol 11. W.A. Benjamin, New York, K . Y . , 1966, p 119. ( 2 ) S. R. Sandler and W. Karo, Orp. Functional G r o u p P r e p . , l a , 363 (1968). (3) F. W. Schueler and C. Hanna, J . Amer. Chem. Soc., 73, 4996 (1951). (4) C. Hanna and F. W.Schueler, i b i d . , 74, 3693 (1952). ( 5 ) 0. Westphal, Ber., 74, 759 (1941). ( 6 ) R.D. Brown and R. A. Kearley, J . Amer. C h e m . Soc., 74,2762 (1950). ( 7 ) E. F. Elslager, E. A. Weinstein, and D. F. Worth, J . .Wed. C h e m . , 7, 493 (1964). (8) A. K. K o s t and R. S. Sagitullin, I-estn. X o s k o u . Cnir., Ser. X u t . 'Vfekh.. Aslron. Fiz., Khzm., 14, 225 (1959); Chem. Absti., 53, 21893 (1959). (9) R . L. IIinman and D. Fulton, J . Amer. C h e m . Soc., 8 0 , 1895 (1958). (10) R. F. Smith, A . C. Bates, -1.J. Battisti, P. G. Byrnes, C. T. hlroz, T. J. Smearing, and F. X. Albrecht, J . 070. Chem.. 33, 851 (1968). 111) R. L. Hinman, J . A m e r . Chem. SOC.,73, 1645 (1956). (12) R . L. Hinman, ibid.,78, 2463 (1956). (13) W.W . Hartman and L. V. Roll, in "Organic Syntheses," Collected Vol 11, W'ilel-, New York, N. Y . , 1943, p 460.
(14) T h e autliors carried oiit rliie reaction o n l..j m o l c ~of .\Lnitrosoamine with 3 moles of L.11-I in a 3-1, %neck flask ivitl>out difficulty. (15) c'. G . Overberper, 1.. (', Palmer, 13. S. I I a r k s , ani1 1. II. I < > rii. J . Bmev. C h t n i . S o c . , 77, 4100 (1955), (16) 11. Zimmer, I.. '1'. .\iidrietli. AI. Ziniincr. and 11. -1. l I u \ ~ ' e ,O j ~ i l . ,77, T9O (1955). (1Tj This \ v a i a 3lodel S l l O dri- gas m e t e r cnlil)rated i n liter;. I t i\-a* designed for propane, butane, or natural gar and was purcliaseil from ltockn-ell Manufacturing Co., hleasurement and c'ontrul I)ivision, I'ittshurgli, P a . 75208. I t \vas fitted n.itll hose ronnections a f t p r purchase.
Journal of Medicinal Chemistry, 1971, Vol. 1.6, N o . 11 1053
MAO-INHIBITORY HYDRAZINES
TABLE I
I
CH < Y
Compd
Z
Method
Yield, %
Empirical formula
B p (mm) (mp of salt) of free base, "C
Analyses
85 (59)" CaHizNz 103-105 (15) c, H 55b 84 C sHi4Nz. HC1 H 1116 2 2-CHa 99-100 (9) (112-113) Cl H 108-110 (3) H I 90 CsHiiClNz 3 2-c1 Cl H I1 92 92 CsHiiClNn.O.5HOzCCOzH 4 3-C1 H I 115-120 (8) (161-163) c, Hl N 110-112 (3) H IIIc 5 4-C1 60 CsHiiClNn Cl H I 80 120-122 (4) H IId 6 2-Br 60'9' C8HllBrZNz c, €3 7 2-CFa H IId 640 CgHiiFaNz 98-102 (12) Cl H 80 CgHirNz0.0.5H02CCOzH 8 2-CHaO H I 85-87 (1) (163-165) Cl Hl N 9 3-CHaO H IIIC 54 CgHirNzO 78-85 (0.275) Cl H I 90 CgHi4Nz0.0.5HOzCCOzH 92-94 (1.5) (159-161) Cl H, N 10 4-CH30 H 11 2-CHsS H I 87 C ~ H ~ ~ N Z S * O . ~ H ~ Z C C101-105 O ~ H (0.6) (156-158) Cl Hl N 12 3-CH3S H IIIC 49 C sHirN nS 93-94 (0.3) c, H 13 4-CHaS H IIIC 66 CgHirNzS 94-96 (0.3) Cl H 14 2-CzH5-A H IId 85 CioHieNzS 93-100 (3) c, H IId 87 CiiHiBNzS 93-99 ( 0 . 5 ) c, H 15 2-i-CaHT-S H 16 2-CaH,-S H IId 85 CiiHisNzS.O.5H02CCOzH 112-113 (0.5) (130-132) Cl Hl N 17 2-Allyl-S H IId 83 CiiHisNzS.O.5HO~CCO~H 81-83 (0.2) (137-139) c, Hl N 18 2-C1 3-CH30 IId 80 CsHisClNnO 102-103 (0.6) Cl Hl N 19 2-c1 3-C1 118 60* CsHiaClzNz 88.5-89.5 (0.375) Cl H 20 2-c1 4-C1 I1 95 CsHioClzNz * HC1 89-90 (0.2) Cl H 2-c1 5-C1 IIC 53 CsHloClzNz 85-88 (0.35) Cl H 21 22 2-c1 6-C1 I1 93 CsHioClzNz 81-84 (0.40) Cl Hl N 23 2-CHa0 IId 75 C I O H ~ ~ N Z O ~ . O . ~ H ~ ~ C 104-104.5 C O Z H (0.45) (142-143) 4-CHaO C, H, N 24 2-CHaO 5-CH30 IId 72 CiaHi6Nz0z 103-104 (0.45) c, H Ci~Hi6NzO2.0.5HOzCCO2H 110-111 (0.45) (141-143) 25 3-CH30 4-CHsO I 87 C, H, N 96-97 (4) 26 2-C1 IId 83 C8HioClFNz 6-F c, H, N 27 2-CHa 3-CH3O IId 70 CioHisNzO 71-72 (0.15) c, Hl N b Ref 12. The yield was based on a This yield was reported in ref 18. The use of insufficient LAH accounts for the poor yield. Yield pure benzoic acid 1-methylhydrazide. c Yield from the starting carboxylic acid. d Yield is from the starting benzyl alcohol. The o,a-dibromotoluene, prepd using NBS contained o,aptribromotoluene by nmr (cc14) and Ois from the starting toluene. bromobenzaldehyde (o-bromobenzy1)methylhydrazone (28) was isolated from the reaction; bp 178-181' (0.65 mm): Anal. (C15Hl4Br2N2) C, H. 0 The o-trifluoromethylbenzyl alcohol with SOC12 (uncatalyzed) in CHCla resulted in incomplete conversion to the chloride. * The reaction of 2,3-dichlorotoluene with Br2 and light gave a mixt of unreacted toluene (29%)1 a-bromo-2,3-dichlorotoluene (58y0), and a,a-dibromo-2,3-dichlorotoluene (13%) by vpc. 1
H
H
I I11
methylhydrazide by this route. This route can be used with any substituents compatible with LAH and any aromatic orientation. The yields are usually considerably lower. Yields are based on isolated, analyzed products, which were used successfully in further reactions. As noted by others,15 hydrazines sometimes analyze with difficulty. If the free base did not analyze satisfactorily, the hydrazines were converted to the hemioxalate or hydrochloride. Biological Results.-Biel and coworkers had found the in vitro inhibition of M A 0 activity of l-benzyl-lmethylhydrasine (1) to be less than that of N-isopropyl-N '-isonicotinoylhydrazine (iproniazid) and much less active than other hydrazines included in their work.18 I n Biel's series of more active compounds, "nuclear substitution generally reduced M A 0 inhibitory activity." A number of the hydrazines prepd in our lab were tested for in vitro M A 0 inhibitory activity using a minor modification of the procedure described by Glowinski, et ~ 1 . ~ In 9 this series, some (18) J. H . Biel, A. E. Drukker, T . F. Mitchell, E. P. Sprengeler, P. A. Nuhfer, A. C. Conway, and A . Horita, J . A m e r . Chem. Soc., 81, 2805 (1959). (19) J. Glowinski, J. Axelrod, and I. Iverson, J . Pharmacol. E z p . Ther., 163, 30 (1966).
nuclear substitutions enhanced M A 0 inhibitory activity. Thus 3, 4, 5 , 6, 10, and 18 were as potent as iproniazide and 1 , 8 , 9 ,and 11 were markedly less potent a t 10-5 and 10-4 M concn. See Table I1 for data. Experimental Section20 In Vitro M A 0 Test Method.-Whole mouse brain was homogenized in 6 vols of ice-cold 0.9% KC1 soln containing 2 mg/ml of Versene. A 0.1-ml aliquot of the homogenate was added to a mixt of 0.3 ml of 0.9% KCl, 0.7 mg/ml of Versene, and 0.55 ml of a soln of the test compd in 0.05 M sodium phosphate buffer of p H 7.3. The mixt was shaken a t 37" for 20 min and 0.1 pg of ~-norepinephrine-methylene-'~C (169 pCi/mg) in 0.1 ml of 2 mg/ml of Versene soln was added to the mixt, and incubation was contd for 45 min. The reaction was stopped by the addn of 1 ml of 0.2 M NaOAc contg 2 ml/ml of ascorbic acid (pH 4.0). The mixt was centrifuged and the supernatent was passed through a column of Dowex 50 ( H + ) 4 X 35 mm. A 1-ml aliquot of the effluent contg the 14C deaminated products was added to 15 ml (20) Melting and boiling points are uncorrected. The mp mere detd using a Thomas-Hoover mp apparatus. Ir spectra were recorded on a Beckman Model IR-9spectrometer. Nmr spectra were recorded on a Varian Associates A-60 mectrometer in CDCla. We wish to acknowledae the following: spectra were obtained by Dr. J. M . Vandenbelt and staff; microanalyses were performed by Mr. C. E. Childs and staff. The redns were carried out in round bottom flasks, equipped with a liquid sealed stirrer, thermometer, pressure equalized dropping funnel, and 8 reflux condenser connected to a dry gas meter.
1054
Journal of Medicznal Chemistry, 1971, Vol. 14, iYo. 11
ARCHIBALD,et al.
T.IRLI:I1 I n J'c'tro IKHIHITION OF I\Iousi- BRAISAIoxo.\msr: OXID.GSE
with caution followed by 20% NaOH (90 ml) and H 2 0 (420 ml). The slurry was filtered, and the filtrate concd arid distd to yield See Table I for physical constants. The yields _____---- Molar concn----7 in Table I are based o n starting nitroso compd. 10-5 5 x 10-5 10-4 5 X 10-4 150" 11.-The benzyl halides were prepd by the reaction of the Test compd benzyl alcohol with excess concd HC1, HBr, or with excess SOC12 Iproniazide 37 88 97 I .5 (pyridine catalysis in CHC13 or 1,2-C2H4Cl,s o h should be used 1 32 i -1 07 2..i particularly for ortho-substituted examples-hee 7, Table I). If ;3 49 92 the t'oluene was the commercial starting material, it. was treated 97 1.0 Kith S B S (used crude after removal of the sliccinimide and CC14) 4 61 90 99 0.4 or with Brg and light.. The presence of the a,a-dibroniotolueiie I .6i 95 100 0.6 i n the S B S product reduces the yield. 6 39 s7 100 1.7 Typical Alkylation of Methylhydrazine with an Ortho-SubS 14 .1 i h6 7.0 stituted Benzyl Halide. 1-(0-Chlorobenzy1)-1-methylhydrazine !I 22 7% 93 3 .5 (3).-To n mixt of methyl hydrazine (161 g, 3.5 moles) arid 10 46 h7 98 1.2 anhyd Et013 was added with stirring o,a-dichlorotoluene 11 17 70 94 4.0 (161 g, 1.0 mole). The mixt was refluxed 1 hr after the temp 1s 6 .i 87 93 100 0 .3 began to fall. 11. was concd in tacuo, made alk (50$; SaOlT), and extd (Etn()). The exts were wahhed with H 2 0 , dried (3IgConcn X lo-" I\. for .iOycinhibition of M A 0 activity. SO4), concd, and dihtd to yield 3, 138 g (92%). See Table I for physical characteristies. The yield$ i n Table I are based o n the starting alcohol or toluene with the exception of 3, 20, arid 22 of scintillation fluid and the radioactivity was measured. A where the beiizyl chlorides were commercial. blank coiitg boiled enzyme was carried through the entire pro111.--The aroyl chlorides were prepd by t,he use of S0Cl2 on the cedure. The reported result's are the averages of replicates and commercial aroni carboxylic :icid.: mid Jvere used crude or were the average variation in the same experiment was i.iyc. The commercially available. T:,o was derived from a graph of the log concn 'per cent inhibition. Chemistry. 1.-The ,\'-nitrosoamines were prepd by t,he Typical Aroylation of Methylhydrazine and LAH Redn of the method of Hartman aiid Resulting Mixt. 1-(na-Methoxybenzy1)-1-methylhydrazine(9). HC1 was replaced by AcOH, -A mist of methylhydrazine (170 g, r3.7 moles) arid HyO (6SO g ) the reaction was carried out under p i p (HONO is lost by reaction ivas cooled l o 0" aiid with stirriiig a solii of crude m-methosywith 0 2 ) , and the niixt was heated to 60-70" after the addn of benzoyl chloride (:300 g, I .76 moles) in T H F (400 mi) was added. the h'nN0, s o h . The compds were distd and anald, but can The mixt was stirred overnight and extd fEt20). The exts were be \wed crude in the redns. The nmr apectra show split X e and dried ( l I g S 0 4 ) ,wncd, arid used crude. A mist of LAH (114 g, CHg peaks. 3.0 moles) and T H F (l,.? 1.) >vas heated t o 30-40" under S,, and Typical LAH Redn of the .\'-Nitrosoamine. 1-( m-Chloroa soln of the (.rude ni-niethoxybenzoic acid I-methylhydrazide iri benzyl)-1-methylhydrazine (4).-A su3pension of LAH (114 g, T H F 1300 nil) vas added dropwise. The H Z evoln was moni3.0 moles) in aiihyd EtpO ( 2 . 2 1.) was heated t o a gentle reflux iiiider Ng, xiid a s o h of ?n-chloro-AV-methyl-L\'-iiitrosobenzylamine tored," and the mist was refliixed overiiight, cooled under N,, and worked up as in I t o +eld 9, 158 g (47r;). (26s g, 1.4,5 moles) in T H F (500 ml) was added dropwise over See Table I for physical data. The yields in Table I are based on the starting aryl :;-4 hr. IT2 evoln began immediately. The mixt was refluxed carboxylic acid o r acid cvliloride if conimercinl. overiiight, cooled wider N2, and H2O (120 nil) was added dropwise 3-
'8
Synthesis and Hypotensive Activity of Benzamidopiperidylethylindoles' J. L. ARCHIBALD,* B. J. ALPS, J. F.C A V A L L A ,
AND
J. L. JACKSOX
John JVzjeth and Brother Lznzited, Taplow, JIazdenhead, Berkshire, England
Receaved March 12, 2971 The bynthesis arid hypot,eiisive activity of a series of indole piperidine amides are described. One member of the series--3-[2(4-benzamidopiperid-l-yl)ethyl]indole (indoramin) (35)-has undergone intensive pharmacological investigation. The sudtained hypoknsive action of 35 is believed to be due t o a combinat'ion of local anesthetic and a-receptor blocking properties.
benzamido derivative 35 (indoramin) was a potent A continuing interest in indole derivat'ives incorpohypotensive agent. Detailed pharmacological invesrating a tryptamine residue as potential antihgpertentigation of 35 has since revealed a combination of propsive agents stemmed from our work with 1,4-bis(inerties that seems likely to be advantageous in the treatdolylethy1)piperidines. In that series, the indolylmerit of cardiovascular disease in ethyl moiety attached to the piperidine 4 position was This compound then became the prototype for a11 riot an essential feature for retention of antihypertensive extensive synthetic program designed to investigate activity. It could, for instance, be replaced without detriment by a 3-carbet~hoxy-2,4-dimethylpyrrol-5-y1-structure-activity relationships and to optimize activity. ethyl group.3 We decided t30 retain the indolylethylpiperidine moiety of the earlier series while varying t'he 4 substituent, of the piperidine ring, concent'rating in particuH lar 011 amino derivatives, which had received little atten35 tion in the past. I t was soon discovered that the 4(1) Presented in part a t the IT International Congress of Medicinal Chemistry, Clermont-Ferrand, France, Sept 1968. J. L. Archibald, Chim. T k r r . , 3, 397 (1968). (2) J. 1., Archibald, T. Baum, and 9 . J. Childresa, J . AJIed. C k e m . , 13, 138 (1970). ( 3 ) .J. L. Archibald, J . Heteroevcl. Chem., 3, 409 (1966).
(4) B. J. Alps, J. L. .Irchihald, E. S.Johnson, and A . B. Wilson, Curdioeasc. Rea., 62 (1970). ( r ) ) B. J. Alps, E. S , Johnson, and .i, 13. Wilson, Brit. J . Phnrmrrcol.,
40, 1 5 l P (1970).
(6) B. J. -41113, RI. Hill, E. S. Johnson, and A . (1970).
n. Wilson, (bid.,40,
153P
