analgesics. some substituted 2,3-dihydro-4-quinolones - j. med. chem., 1965, 8 (5), pp 566–571

8/4/2019 Analgesics. Some Substituted 2,3-Dihydro-4-quinolones - J. Med. Chem., 1965, 8 (5), pp 566571

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September 1965 2,3-DIHYDRO-4-QUINOLONES S ANALGESICS 567by the 6-elimination of the aminc f rom the p-anilino-propionic acid. Cyclization of a p-anilinobutyric acidto the corresponding 2,3-dihydro-4-quinolone had beenr e p ~ r t e d , ~ut the geiierality of this reaction was no trpalized until this work was in progresyntheses of 2,3-dihydro-4-yuiiiolo11esiivolved cycliza-tion of 0-(arenesu1fonamido)propionicacids by meansof a variety of reagents, followed by vigorous hydrolysisof the l-(arenesulfonyl)-2,3-dihydro-4quinolone to give

The cyclization by means of polyphosphoric acid wassuccessful in almost all cases, but could not be eniployedfor the synthesis of those compounds containing anallyl or benzyl group on the heterocyclic nitrogen atom.When X-benzyl- or N-allyl-p-anilinopropionic acid washeated in polyphosphoric acid, only 2,3-dihydro-4-quinolone could be isolated. The S-allyl and N-benzyl compounds were prepared by heating alcoholicsolutions of 2,3-dihydro-4-quinolone with allyl orbenzyl chloride. The alkylation of I was successfulwhen small quantit ies of Triton B were added t o thereaction mixture but did not yield alkylated productswhen sodium carbonate or sodium bicarbonate wassubstituted for the Triton B. Similar alkylations ofthe alkoxy-', ,3-dihydro-4-quinolones with methyl iodideprovided a more satisfactory synthesis of their N-methyl analogs than did the cyclization of the cor-responding p-anilinopropionic acids.While the cyclization of o ~ t h o -o r pia-substituted6-anilinopropionic acids could give rise t o only oneproduct, those with substituents in the nzetu positioncould yield either 5- o r 7-substituted 2,3-dihydro-4-quinolones. Braunholtz and AIann* and Huisman andco-worliers10 had previously examined the structure ofthe product obtained by the cyclization of p-(S-p-toluenesulfonyl-m-anisidin0)propionyl chloride. Al-though some disagreement exists concerning the pres-ence of both possible isomers in the reaction mixture,it was agreed by both investigators that the chiefproduct of the reaction was 1-(ptoluenesulfony1)-7-methoxy-2,3-dihydro-4-quinolone.While it wasexpected that the polyphosphoric acid-catalyzed cycli-zation of p-(m-anisidin0)propionic acid would yieldchiefly 7-methoxy-2,3-dihydro-4-quinolone,he n.m.r.spectrum of this product was examined to ob-tain unequivocal proof of its structure. The spectraappeared to be in agreement with that reported byHuismanlob and Smith" and was used by us to es-tablish th e structure of the 7-ethoxy analog I (R' =

We were interested in introducing a group in the 3-position of the 2,3-dihydro-4-quinolones. n attemptt o carry out a Mannich reaction with 1-(p-toluenesul-fonyl)-2,3-dihydro-4-quinolone1ormaldehyde, and di-ethylamine yielded only start ing materials. i\Iann,I2

1 . 3 6-10

R" = H).

(4) J. Koo, J . Oro. C h e m . , 2 6 , 2440 (1961).(5) J. Koo. ib id . , 28, 1134 (1963).(6) (a) G. . Clemo and W.H. Perkin, J . Ch em. Soc., 125 , 1608 (1921):(7) (a) R.C. Elderfield, et al., J . A m . Ch em. S oc . , 68 , 1259 (1946); (b)(8) J. T. Braunholtz and F. G. Mann, J . Ch em. Soc. , 4166 (1957).(9) C.D. Hurd and S. Hayo, J . A m . C h e m . S oc . , 76 , 5065 (1954).(10) (a) W.N. Speckamp, U. K. Pandit , and H. 0. Huisman, R e c . t rau .(h) Tetrahedron Let ters . 44,3279 (1964).(11) H. Smith, G. H. Douglas, and C. R. Walk, Ez pen 'en t ia , 20 , 418

(b) i b id . , 127,2297 (1925).ibid. , 71,1906 (1949).

c h i n . , 8 2 , 39 (1963);(1964).

n7ho attempted the Maiiiiich reaction directly onl-methyl-2,3-dihydro-4-quinolone,bserved that 1,3-dimethy1-2,3dihydro-4-quinolollc rather thaii theexpected JLiiiiii(~1i az e i v a h foriiied.I n vien of the fai lure n-ith the llanri ich Reaction, itwas decided to at tcnipt to alkylate t h e ketone t'zu theenamine. Attempts to prepare the enamine by thedirect reaction of pyrrolidine and l-niethyl-2,3-dihydro-4-quinolone resulted in the isolation of starting prod-u c t ~ . ' ~n order to increase the electrophilic naturcof the carbon of the ketone group,13 thus facilitntiiigattack by an amine, l-(p-toluene~ulfonyl)-2,3-dihydro-4-quinolines was treated with pyrrolidine and readilyformed an enamine [11,R = H; R ' = p-S0&6H1CH3;

NR,"I 0I/

IR'I1

IR'I11

R" = (CHB)4] .Compound I1 was alkylated by ethylacrylate, but acrylonitrile and acrylaniide did not react.The resulting ethyl l-(p-toluenesulfony1)-3-(2,3-dihy-dro-4-quino1one)propionate mas hydrolyzed to give 3-(2,3-dihydro-4-quinolone)propioniccid (111,K = R ' =

The enamine from 1-(p-toluenesulfonyl)-8-niethoxy-2,3-dihydro-4-quinolone and pyrrolidine was siniilarlyprepared, but the 7-methoxy analog failed t o react withpyrrolidine. The enamine of l-p-toluenesulfonyl-8-methoxy-2,3-dihydro-4-quinolone as successfullyalkylated with ethyl acrylate and the product washydrolyzed by acid to the corresponding acid I11 (R =3-(2,3-Dihydro-4-quinolone)propionicacid and its8-methoxy analog were converted to the correspond-ing amides (Table 111) via reaction of their nixed an-hydrides with ammonia or amines.3-(2,3-Dihydro-4-quinolone)propionpyrrolidideuponreduction with LiA1H4 yielded 3- [3-(X-pyrrolidinopro-pyl) ]-1,2,3,4-tetrahydro-4-quinolinol.Biological Activity.-All of the compounds synthe-sized as well as the known 6-11iethyl-~~ nd i-chloro-

2,3-dihydro-4-quinolones13hich were niade by therespective literature methods, were examined for anal-gesic activity using the Haffner tail pinch niethod14

H; X = COZH).

8-OCH3; R' = H ; X = COZH).

(12) P. I. Illyersh and F. G. Mann, J . Ch em. S O L ,467 (1Q58).(13) It has been postulated that the yelloa calor of this ketone ( A ) might

he explained b y the ability of the compound to exhibit tautomerism and toexist as structure B.6bsE Structure C has also been suggested to he responsi-bl e fo r the yellow co1or.a This dipolar structu re (C ) would not favor enamineformation. It s contribution would be inhibited if an electron-attractinggroup were attached to the nitrogen atom (see structure D).

IS0,Ar.. 'CH,, I @CH, CH,3A B C D

(14) C. Bianchi and J. 1:ronclieshini. Brit. J . PIKZT~KZCOZ.,, 2 x0 ( 1 9 5 4 ) .


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568 Vol. 8

RH

HHHHIHH16-OCH36-OCH37-OCH87-OCHa7-OCH,8-OCHj8-OCHj6-OCzHj7-OC?HjS-OC?H,

h l e t l i odh

xBb.'IAA13

CHi-CHCH? BH ACHJ BH ACH3 BCsH5CHz BH ACH3 BH AH AH A

Temp., Time,o r .130

13514514 5150

151)

. . .

. . .135. . .125. . .. . .15013813 5

14 0

. . .

}IT.0 5

34512

1313I 319

240 7


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September 1965 2,3-DIHYDRO-4-QUIXOLONES S ANALGESICS 569

Derivative"HB r2,4-D N P3,5-DNBHB r2,PDNPHB r2 , P DNPHB r2 , P DNPHB rHB r2,PDNPHBrPicrate2 , 4DNP2, P DNP2, P DNP2,PDNP

2,4-DNP

2,4-DPjP

2,4-DNP

HBrHBrHB r

HBr2,4-DNP2,4-DNP

Crystn.solvent

Methanol-etherAcetic acid95% EthanolMethanol-etherAcetic acidChloroform-etherAcetic acidChloroform-etherAcetic acidChloroform-etherAcetic acidChloroform-etherAcetic acidChloroform-etherAcetic acid9570 EthanolAcetic acidAcetic acid

m p . , "C .185274-276213-214177-178244-245184-186246-248174-176220-221138-139166-167149-151176-178157-158210-2112 10-2 11190-192290-293254-255264-266e241-242

20&202181-182178-179215-2 16208-210271-272

--Found, Yo---alcd.. %C

47.3955.0556.3149.6056.3051.5857,4653.3458.5354.9259.5256.3860.4460.3763.3051.93. . .. . .54.9853.7854.98

46.5248.5448.5454.9848.5454.98

H4.424.003.254.994.435.514.825.975.186.385.526.675.835.074.593.87. . .. . .4.614.234 . 6 1

4.685.185.184.615.184.61

N6.1421.4012.315.7820.525.4719.715.1818.964.9218.274.7017.624.4016.78

13.4619.0619.6018.8619.6018.86

5.435.145.1418.865.1418.86

C47.3555.1756.3849.4756.4051.7057.6153.4158.6955.0259.6756.2760.5060 .3263.4851.51. . .. . .54.9253.9955.09

46.5948.7248.6255.1148,5755.09

H4.414.173.555.124.595.674.996.015.326.465 . 636 , 9 l6 .015.104.603.85. . .. . .4.534 . 114.76

4.585.285.264.645.174.70

N6.2821.4112.455.8020.045.3620.025.3019.035.0118.414 . 8817,704 . 4516.72

13.3318.5819.9018.9119.5018.85

5.395.145.2018.705.1418.86

Acetic acidAcetic acidAcetic acid

Methanol-etherRIethanol-etherChloroform-etherAcetic acidMethanol-etherAcetic acid

d Lit.8JOa m.p. 139". 6 Lit.* m.p. 274". f Recrystallized from benzene-methanol.

r.p., oc. Formula C - Found yoC H N--Calcd., %H Nrystn. solvent

156-1 58 CloH14BrN02 46. 16153-154 CllHlsBrNOz 48.18158-160 ClzH18BrNOz 50.00150-151 ClaHZoBrNOz 51.65136-138 CI4HzzBrNO2 53.16

Methanol-etherMethanol-etherChloroform-etherChloroform-etherChloroform-ether

5.42 5.415.88 5.116.29 4.866.67 4.637.01 4.43

46.21 5.61 5.5448.03 6.05 5.0750,00 6.25 4.6851.75 6.77 4.76.53,00 6.93 4.52

Chloroform 124-125 CIOHllBrNOI 43.50 ,5.11 5. 07 44.04 5.07 5.16

terial was wed in the next step of the synthesis. e Lit.7~m.p. 87-88".


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570

Experimental 6General Procedure for the Synthesis of p-AnilinopropionicAcids.--A solution of the appropriate aniline (1.0 mole) in areto-nitrile (500 ml. was heated to 81-83". Propiolacitoiie (1.0iriole) was added gradually with stirring over a period of 20-30

r i i i i i . The heating and stirring was continued for 2-3 hr. aftrrwhich t ime the solvent was removed in UUCILO on a steani bath.Tlie oily residue was dissolved in water (400 nil.) containing 40 g .rif NaOH. Th e resulting solution was cooled in an ic e bath andextmct ed several times wi th ether to remove unreacted aniline.The aqueous layer was acidified with HC1 (1 1) to pH 4-5 toprecipitate the P-anilinopropiorli(. ircid. This mix ture was ex-t iw ted seveml times with ether, :md the iirg:tnic phase wrne

(1.5) ( i . \Vwlfe an d .I , L). 1IarJ)unzld J . l'lruimnrol. l , :xptl . T l i p i a p . . 80 ,( 1 6 ) .ill iiielting points ar e corrected and n e r ~ etermined b y th e tal,-

illary tube niethod using a Thomas-Hoover capillary melting point aplia-r a t u s . Microanalyses were performed h y Ilr. Kurt Eiier. Lahorotoirehlicrochiniiqiie. ficole d e Chimie, G e n P v e , Switzerland, and by h l i c r o - T e c l iLaboratories, Skokie , Ill. N .m r. spectra wrre determined o n a VariaiiAssociates A-60 ngectromet.Pr, and infra red slxctrii on it I'erkin-I


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Sept'eniber 1965 A N T I T U S S I V E ESTERSF BASIC 4LCOHOLS 5710.12 mole), and p-toluenesulfonic acid (1.0 g.) in anhydrousbenzene (100 ml.) was refluxed for 18 hr. as described under thepreparation of l-(p-toluenesulfonyl)-4-(X-pyrrolidino)-1,2-di-hydroquinoline. When the solvent was removed and the residuewas recrystallized from methanol, a crystalline solid (10.0 g., 6i c o )melting at 141-142' was obtained.A n a l . Calcd. for C21H24N?OaS: C, 65.60; H, 6.29: N , 7.28.Found:3-(2,3-Dihydro-4-quinolone)propionic cid.-1-(p-Toluene-sulfonyl)-4-(?;-pyrrolidino)-l,2-dihydroquinoline (10.6 g., 0.03mole) was treated with ethyl acrylate ( 9.0 g., 0.09 mole) inboiling methanol (100 ml.) for 20 hr., after which time water (10ml.) was added, and the mixture boiled for another hour. Afterremoval of the methanol , the residue was extracted with ether,and the ether layer was washed with .5YCHC1 and dried (Na2 S04).The residue ('3.0 g. ) could not be crystallized nor distilled inz ' a c ~ ~ and was immediately hydrolyzed by boiling with HCl( 3 0 nil.) in acetic acid (30 ml.) and water (10 nil.) for 4 hr.Solvents were then removed in zlacuo, and the residue was ti-trated with water (10 ml.). The solid was recrystallized fromethanol-ether to give crystals (4.3 g., 65Yo based on the enamine),m.p. 160-161".A n a l . Calcd. fo r CleH13K03: C, 65.74; H, 5.98; N, 6.39.Found:3-(8-Methoxy-2,3-dihydro-4-quinolone)propionic cid.-When a solution of l-(p-toluenesulfony1)-4-(L";-pyrrolidino)-8-methoxy-l,P-dihydroquinoline (3.8 g., 0.1 mole) and ethylacrylate was boiled in methanol (100 nil.) for 20 hr. and workedup as described for the 8-desmethoxy analog, an oil (1.5 g.) wasobtained. Hydrolysis of a 4.3-g. sample of such an oil was

C, 65.04; H, 6.16; N , 7.57.

C, 65.T4; H, 5.95; K, .39.

carried o ut wi th HC1 (4.0 ml.) in acetic acid (12 ml.) an d wat,er(4.0 ml.) a t reflux for 4 hr. Evaporation of the solvents and t headdition of water (5 ml.) gave the product which crystallizedfrom et'hanol-petroleum ether ( 1.5 g., GO%), m.p. 139".A n a l . Calcd. for CIIHIINOI: C, 62.64; H, 8.07; N , 5 . 6 2 .Found:Amides of 3-(2,3-Dihydro-4-quinolone)propionicAcid and the8-Methoxy Analogs.-To a suspension of acid (0.005 mole)in 100 ml. of anhydrous ether was added triethylamine (0.5 nil.).The resulting mixture was cooled to 5' and treated with ethylchlorocarbonate (0.005 mole) and the n s tirred for 15 min.Ammonium hydroxide (5.0 ml.) or the amine (0.02 mole) wasadded, and the niixhre was stirred an additional 15 niin. Theprecipitated amide was removed b y filtration, washed with water,and dried . The amides were purified by recrystallization fromthe designated solvent (see Table IV).3- [3-( -Pyrrolidinopropyl)] -1,2,3,4-tetrahydro-4-quinolinol.-To a solution of 3-(2,3-dihydro-4-quinolone)propion-K-pyrrolide(2.7 g., 0.01 mole) dissolved in tetrahydrofuran (40 ml.) wasadded in small quantities LiAlH, (1.5 g., 0.04 mole). The re-action mixture was warmed to 55-60' and stirred for 20 hr., atwhich time the excess LiAlH, n-as decomposed with 5% SaOHsolution. Tetrahydrofuran was removed by distillation, and thereaction mixture was diluted ivith water and extracted three timeswith ether. The combined ether extracts were dried (l Ig S0 4) ,and the solvent was removed by distillation. The residue afterrecrystallization from ether weighed 1.25 g. (4847,) and meltedat 108".

Anal. Calcd. for C16H?4N?O:C, 73.84:H, 9.29; S , 10.76.Found:

C, 62.62; H, 6.01; S , 5.61.

C, 73.X; H, 9.44; N , 11.00.

Che mistry an d Pharmacology of Some Esters Derived from Basic AlcoholsF. P. DOYLE, '~1.D. ~ I E H T A , ' ~. WARD,'^ J . BAIKBRIDGE, '~SD D. 11. BRO W K ' ~

Beechain Research Laboratories, Brockham P ark , Retchworth , Sur rey , Eng landReceived March 25 , 1965

The preparation of a number of a- alk oxy-apdip henyla cetates derived from open-chain basic alcohols isdescribed. Some of these compounds possess antitussive activity comparable to th at of codeine phosphate andof th e same order as tha t of their analogs which contain pyrrol idine or piperidine rings. 2-Diethylamino-l-( 01-methoxy-a,a-dipheny1acetoxy)propane rearranged on heating to l-diethylamino-2-(01-methoxy-01,~-diphenyl-acetoxy )propane.Chemistry.-2-Dimethyl- and 2-diethylaminoethyla-alkoxy-a, a-diphenylacetates have been claimed topossess useful local anaesthetic, analgesic, or anti-spasmodic activity.2 In a previous publication3me have described the preparation of some promisingantitussives in which a number of a-alkoxy-a,a-diphenylacetic acids were esterified with a range of 1-alkylpyrrolidinyl or 1-alkylpiperidyl alcohols. I n orderto determine if a ring structure in the basic par t of themolecule i5 essential for antitussive activity, meundertook the preparation of closely related com-

pounds derived from open-chain basic alcohols car-rying similar or different alkyl groups on the nitro-gen atom. The basic esters were prepared frommethyl or ethyl esters of the a-allioxydiphenylaceticacids by transesterificatioti with the appropriateamino alcohol.

During this synthetic work we observed the thermalrearrangement of 2-diethylamino-1-( a-methoxy-ala-di-pheny1acetoxy)propane (I) to the isonieric l-diethyl-amino-2- (a-methoxy-a ,a-diphenylac etoxy)propane (11).AR-CH2CHKEtz + RCHCHzNEt2Ih l eII I1

I and 11,R = Ph2C(ORIe)C02This rearrangement amplifies our earlier studiesof the ester of the related 1-alkyl-2-hydroxymethyl-pyrrolidines4" and complements tha t of Kerwin,

e t aZ.,4b n 1-chloro-2-dialkylaminopropane.

Me

Experimental(1) (a) Chemistry Department; (b) Pharmacology Department.(2 ) A . Gilman, L . Goodman, J. M. Thomas, G. A . Haln, and J . M. Prut t -

ing J . Pharmacol. Ezptl. Therap., 74, 290 (1942); R.Hirt , H d u . Chi n. Ac ta,32, 87 (1949); Wander, A. G.. British Patent 641,571 (1950): BoehringerSohn, British P aten t, 716,700 (1951); J. Biichi, H. Lauerner, R. Meyer, andJ . Am. Chem. Soc., 7 6 , 3161 (1954); J. Klosa, Arch. Pharm., 287, 321(1964); 288, 42 (1955).

(3) F. P. Doyle, M. D. Mehta, G. S. Sach, R. Ward, and P. S. Sherman,J . Chem. SOC., 78 (1964).

Melting points were determined in open glass capillaries usinga Buchi apparatus and are uncorrected. The infrared absorptionspectra for th e ester rearrangement s t,udy were obtained by Rfr.K. Austin using a Grubb-parsons spectrometerR, Lieherherr, Hel o , Chim, Acta, 34 , 37 3 (1951); F, , licke and J, H, Biel, wit'h the specimens " '% in CHC18.

(4 ) (a) E. G. Brain, F. P. Doyle, and M. D. hlehta, ibid., 633 (1961);(b ) J. F. Kerwin, G. E. Ullyot, R. C . Fuson, and C. L. Zirkle, J . Am. Chem.Soc. , 69 , 2961 (1947).

analgesics. some substituted 2,3-dihydro-4-quinolones - j. med. chem., 1965, 8 (5), pp 566–571

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