PIPERIDINE DERIVATIVES. PART 1. LOBELAN AND RELATED

[CONTRIBUTION No. 23 FROM THE RESEARCH LABORATORIES OF HOFFMANN-LAROCHE, INC.]

PIPERIDINE DERIVATIVES. PART 1. LOBELAN AND RELATED COMPOUNDS JOHN LEE

AND

WERNER FREUDENBERG'

Received July 88,lQq.4

Lobelan, l-meth~1-2~6-diphenethylpiperidine (Ia), the parent alkaloidal base from which the chief alkaloids of Lobelia inflata, lobeline, lobelanidine, and lobelanine can be considered to be derived, contains inherent in its structure di(y-phenylpropy1)methylamine (IIa). Similarly, lobelanidine (Ib) inherently contains the corresponding secondary alcohol (IIIa). The di(phenylaJky1)alkylamines of the structure 11, in which n is 2 or 3 and m is 1 to 3 and R is an alkyl group, are characterized by interesting and, in some cases, powerful physiological action. Such compounds have been synthesized by Kiilz et al. (1)with variations such as branching of the alkylene chain and substitution in the phenyl nuclei. These compounds are said to exhibit spasmolytic activity. One of them, di(y-phenylpropy1)ethylaminehydrochloride (IIb), has been introduced into medicine as papaverine substitute (2). Blicke et al. (3) have recorded a similar study with some further variations, notably in the use of a cyclohexyl group in the place of phenyl groups, and di(/3-cyclohexylethyl)methylamineis stated to be a powerful spasmolytic substance. An extensive pharmacological report on it has been made (4). It is of interest that Kindler ( 5 ) finds di-(P-phenylethy1)aminesto have a high killing activity against paramecia and other organisms. There seems, to be, however, no report on the corresponding tertiary amines of the structure I1 in this respect. Kulz and Rosenmund ( 6 ) claim that di-(w-phenyl-w-hydroxya1kyl)alkylamines (111), where the hydroxyalkyl chain may be branched and contains not more than 3 carbon atoms and R is hydrogen or alkyl, have a respiratory stimulating effect. This is not surprising in view of the relationship of the amines I11 to lobelanidine. Furthermore, it might be pointed out that the phenylalkylamines I1 (n = 2, m = 2) are inherently contained in derivatives of the opium alkaloid papaverine. This alkaloid and its tetrahydro derivative have a direct spasmolytic action on smooth muscle and in view of the structural relationship, the physiological action of I1 is not surprising. Rosenmund et al. (1) appear to have proceeded in their syntheses from this concept. There seems to be no indication in the literature that the lobelia alkaloids themselves are characterized by spasmolytic action, and in view of the activity of the compounds of the structure IIa in this respect, it was thought of interest to investigate further lobelan and some of its new derivatives. The direct synthesis of lobelan itself has not been previously reported, although it has been made by a partial synthesis from lobelanidine (7). The methiodide of lobelan has been prepared by Wieland et al. (8) by the reduction of 2,6-diPresent address: General Aniline Works, Inc., Linden, N . J. 537

538

JOHN LEE AND WERNER FREUDENBERG

styrylpyridine with sodium and alcohol to 2 ,6-diphenethylpiperidine, separation of the cis and trans isomers formed and alkylation of the former with methyl iodide. We have found a convenient method for obtaining lobelan in the following route, adapted from the method employed by Winterhalder and Scheuing (9) for the synthesis of lobeline. C Ha

I

R1

R1

R*

Ra

H

H

H

b

OH

H

H

a

H

H

H

d

H

H

H

0

H

H

H

f

H

H

H

g

H

H

OCH,

h

H

H

OCHI

i

H

H

OCHa

i

H

H

OCH,

k

H

OH

OCHi

1

H

0

I&

\ m

H

H

/ O CHn

OCHs

2,6-Distyrylpyridhe (V, R = H), treated with methyl p-toluenwulfonate, yields l-methyl-2,6-distyrylpyridinium p-toluenesulfonate (VI, R = H). This quaternary compound can be hydrogenated catalytically using platinum, palladium-carbon, or Raney nickel. The absorption of five molecules of hydrogen occurs readily and l-methyl-2 ,6-diphenethylpiperidne (VII, R = H) is obtained. The melting point of the hydrochloride (195-196") was found to be identical with that of the hydrochloride obtained from the natural alkaloid. Because of the asymmetry of the carbon atoms 2 and 6 in the compounds VII, cis (meso) and tram (dl) stereoisomeric forms could form. Lobelan is known to be the meso form and in this synthesis no other form was isolated, but the mother

539

LOBELAN AND RELATED COMPOUNDS

liquors in the last step were not thoroughly investigated. In the case of the compound VI1 (R = OCH3), two isomeric forms were isolated. That occurring in the greatest quantity easily forms a hydrochloride and other salts. Oxidation of this form to obtain scopolic acid (meso form) by the known methods was not successful. p-Methoxybenzoic acid can be easily isolated, but apparently the conditions required to destroy the saturated side chain are vigorous enough to degrade the piperidine ring. 'o(CHs)n-N--(CH

-

*

I

)

/-\\

"U

IIa n = 3, m = 3, R = CHI b R = CeH6, n = 3, m = 3

R I1

/-\\

CHOH( CH2)n-N-(

u

CH2)mCHOH-

I

/-\

u

1Ila

11 = 2 m i 2

R

111

N

CHt-CHn

/-\-Ftz -\==/

I

R'

IV R1

R'

R8

IVa

CzHs

H

H

b

CHs

H

CHzCH2CsHb

C

CzHs

OCHs

CHpCHzCsELOCH,(p)

d

CHI

H

CHs

e

C2HS

H

CHgCHzCsHs

In the case of the other form only a viscous oil was obtained. Attempts to resolve the material with d-tartaric, d-malic, or d-dibenzoyltartaric acid failed, as crystalline salts were not obtained. A crystalline hydrochloride, m.p. 60°, was prepared. By an analogous reaction scheme, the variously substituted derivatives of lobelan (IC,d, e, f , g, h, i, j, k) can be prepared. Similarly, 2 ,Pdisubstituted piperidines of structures IVb, c, d, e were prepared from 2,4-dimethylpyridines. One of these compounds, l-methyl-2,4-di-(pphenethyl)piperidine, is interesting as an isomer of lobelan. The 2-substituted piperidine, IVa, was obtained from 2-picoline. As an alternative synthesis, the styrylpyridines can be hydrogenated catalyti-

540


V

R

H, OCHa

CHs VI1

cdly to corresponding phenethylpiperidines and then alkylated. This route is not so convenient, since considerable formation of quaternary compounds occurs and several crystallizations are necessary to separate tertiary amines from them. Compound If was prepared by this route by reaction of 2,6-diphenethylpiperidine with ethylene chlorohydrin. This material was also prepared by the reaction of 2,6-distyrylpyridine with 8-benzyloxyethyl-p-toluenesulfonat e and hydrogenat ion of the resulting quaternary compound. In this case the benzyl group also suffers hydrogenolysis. Attempts to combine P-methoxyethyl- and P-ethoxyethyl-ptoluenesulfonates with 2,6-distyrylpyridine failed. Attempts t o prepare 2,6-di-(2-furylidene)pyridirieby refluxing furfural with 2,6-lutidine in acetic anhydride were unsuccessful. The hydrochlorides of the final compounds are not very soluble in water. Other salts of the most promising compound from the physiological standpoint, namely, l-methyl-2,6-di(p-methoxyphenethyl)piperidine,\yere prepared. Of these the ethanesulfonate proved the most satisfactory, having a solubility of 6.7% in water at 25",as compared with 0.6% for the hydrochloride. PHARMACOLOGICAL RESULTS

The pharmacological work on the compounds described was carried out by Dr. R. H. K. Foster, of the Pharmacological Laboratories, Hoffmann-LaRoche, Inc., and will be described in detail elsewhere. In general, the compounds show both a neurotropic and musculotropic action. The neurotropic activity of the most favorable compound, Ih, is about one-tenth of that of atropine, whilst the musculotropic action is at least 7 times that of papaverine when tested against histamine-stimulated intestinal strips. Lobelan, Ia, itself has a slighter neuro-


541

tropic effect and a similar musculotropic activity. However, the relative safety (therapeutic index/therapeutic index of standard compound) by both subcutaneous and intravenous routes is 2.5 for lobelan and 5-6 for Compound Ih, when that of papaverine is given as unity. As was expected from the relationship of the compounds to lobeline, the compounds show in part considerable analeptic activity. This was determined 5bs the respiratory percentage increase in minute volume using a constant amount (2 mg./kg.) in morphinized rabbits. In this respect, increasing the size of the X-substituent decreases the activity; the most potent compound being Ig, which was more active than lobeline. The activity of Ih was of the same order as lobeline. When tested for broncholytic action on isolated guinea pig lung stimulated with histamine, the effect of Ih was about one-twentieth of that obtained with adrenalin. On intact cats, the effect was of the same order. EXPERIMENTAL RESULTS

The general procedures used were similar throughout the series and, therefore, the preparation of one or two members only of each group of intermediates is described. The characteristics of the intermediates and final products are given in Tables I, 11,and 111. &,6-DistyryEpy~idine.2,6-Distyrylpyridine was prepared according to Shaw (lo), or more conveniently, by adopting the method of Clemo and Gourlay (ll),used for the preparation of 4-styryl-2-methylpyridine. This procedure was also used for the preparation of 2-styrylpyridine and 2,4-distyrylpyridine; a further example is the preparation of 8 , -6Di-(p-methoxyphenethenyl)pyridine.Twenty-four grams of 2,6-lutidine, 60 g. of anisaldehyde, and 50 g. of acetic anhydride were refluxed together for sixty hours. The reaction mixture completely solidified on cooling. It was transferred to a suction filter and washed with alcohol. The filtrate and washings yielded only a negligible amount of the di-substituted material. The substance was recrystallized from benzene; yield 36 g.; m.p. 181-182". The mother liquors contain considerable amounts of 2-(p-methoxyphenethenyf)-6-methylpyridine. After removal of the solvents, the residue refluxed with a further 30 g. of anisaldehyde and 50 cc. of acetic anhydride gave a further 10 g. of the desired product. Total yield 61% of theory. 8,6-Di-(p-rnethoxyphenethyl)piperidine. 2,6-Di(p-methoxyphenethyl)piperidinewas obtained by dissolving 1.9 g. of the above compound in 20 cc. of glacial acetic acid and hydrogenating in the presence of two per cent Adams catalyst a t atmospheric pressure. After filtration and evaporation in zlacuo, the residue was crystallized from absolute alcohol; m.p. 154-155". The free base was dissolved in ether, hydrogen chloride gas passed into the dry ether solution when immediate crystallization of the hydrochloride took place. It was recrystallized from alcohol, m.p. 209-211". &,6-Di-(p-methoxyphenetheny1)pyridinemethyl-p-toluenesulfonate. Ninety grams of 2,6-di(p-rnethoxyphenethenyl)pyridinewere heated in an oil-bath with 53 g. of methyl p-toluenesulfonate a t 160-180" for eight hours. The product, after cooling, was washed on a filter with cold acetone and recrystallized from methanol; yield 130 g., m.p. 242-244'. cis-i-Methyl-9,6-di-(p-methoxyphenethyl)piperidine hydrochloride. Twenty-two grams of the quaternary ammonium compound described above was dissolved in a mixture of 50 cc. of absolute alcohol and 50 cc. of glacial acetic acid and hydrogenated a t 50 lbs. pressure in the presence of 1-2% Adams platinum oxide catalyst. The theoretical absorption of H, occurred in about fifty minutes. The catalyst was filtered off and the solvent removed by evaporation in vacuum, mixed with saturated sodium carbonate solution and taken up with warm benzene, washed with water, dried over K&Oa, and dry hydrochloric acid gas passed into the solution. On standing, the crystalline hydrochloride separated and was

542


recrystallized from the minimal amount of methanol or acetone. The melting point of the hydrochloride was 176-178", and the yield was 8.4 g. The above reduction can also be performed with Raney nickel at 50-1000 lbs. pressure. cis-i-Methyl-S,G-di-(p-methoxyphenethyl)piperidine base can be obtained by neutralizing 10 g. of the aqueous solution of the hydrochloride to phenolphthalein, extracting with ether, washing with water, and drying over solid KOH. On removal of the ether, the material crystallizes. The product was recrystallized from minimal amounts of petroleum ether. The melting point is 73-74", yield 8.6 g. TABLE I PYRIDINE DERIVATIVES COYPOUND

APPEARANCE

"c

M.P. UNCOBR

CBYSTALLIZED PROM

EMPIRICAL FORMULA AND M.W.

Found Calc'd

-__

2,6-Di- (p-methoxyphenethenyl) 2- (p-Me thoxyphene thenyl)-6-methyl2- (p-Methoxyphenethenyl) -6-methyl- hydrochloride 2-(3,4-Methylenedioxyphenethenyl) 6-methy1 2,6-Di-(3-hydroxy-4methoxyphenetheny1)2,6-Di - (3,4-met hylenedioxyphenetheny1)2,4-Distyryl2,4-Di- (p-methoxyphene thenyl) 2,4-Di- (p-methylene dioxyphenethenyl) -

Yellow 183-181 needles Small 59-62 yellow needles Bright 103-101 yellow crystals Colorless 114-lll crystals

Ethanolbenzene Ether Aqueous HCl Ethanol

4.34 4.08 6.33 6.22 CiaHiaNO*HCl 261.7

5.9

5.35

6.06 5.83

Yellow crystals

147-14; Ethyl acetate

3.76 3.73

Yellow crystals

L95-19( Benzene

3.68 3.77

Colorless crystals

174

Ethanol

!05

Ethanol

3.95 4.08

!15

Ethanol

3.87 3.77

Yellow crystals

-

The lactate was prepared by mixing molecular parts of lactic acid and the ether-alcohol solution of the free base. On evaporation to dryness, a thick, colorless syrup remained which was decomposed by water yielding the free base. The tartrate was obtained by mixing an alcohol solution of 0.5 mole of tartaric acid with an alcohol-ether solution of 1.0 mole of base. On removal from the solvent and standing in a desiccator over PzOs, the material crystallized. Recrystallized from ethyl acetate, the compound melted at 124-125". It is soluble in water to the extent of about 1.6%. The citrate was prepared i n the same manner as the tartrate, using 4 mole of citric acid per mole of base. The product was recrystallized from benzol; m.p. 149-150'. It is soluble i n water to the extent of about 0.2%. The ethanesulfonate was prepared by treating 1 mole of the base with 1 mole of ethanesulfonic acid in absolute alcohol and evaporating to dryness. A white crystalline product remained which was recrystallized from benzene (or ethyl acetate); m.p. 119-120". The

543


ethanesulfonate is very soluble in alcohol and soluble to the extent of about 6.7% in water at room temperature. cis-l-Methyl-d,6-di-(,9-phenethyl)piperidine(lobelan). Four and five-tenths grams of 2,6-distyrylpyridine methyl-p-toluenesulfonate was suspended in methyl alcohol and hydrogenated using 2% Adams platinum oxide catalyst a t atmospheric pressure. The hydrogenation was complete after three hours. The catalyst was filtered off, the solvent removed in vacuum, and the remaining oil, which showed no tendency to crystallize, was taken up in ether, and dry hydrochloric acid gas introduced. The colorless, oily precipitate which separated crystallized after standing for a few hours in the ice-box and was crystalTABLE I1

PYRIDINIUM ~TOLUINEBULRONATES COHPOUHD

2,6-Distyryl-N-ethyl 2,4-Distyryl-N-me thy1 2,4-Distyryl-N-ethyl 2,6-Dimethyl-N-methyl 2,6-Di- (p-methoxyphenetheny1)-N-ethyl 2,6-Di-(p-me thoxyphenethenyl)-N-bensyloxyethyl 2,6-Di-(phene thenyl) -Npropyl 2,GDi- (methoxyphenethenyl) -N-methyl 2-Styryl-Nethyl

.4PPEAPANCE

Yellow crystals Yellow cubes Yellow crystals Yellow crystals Yellow needles

&P.C:o

C

P

Y

S

~

~

N

EYPIPICAL FOPHULA ~ ~AND D Y.W.

Found

Zalc’d.

232-234 Methanol

2.78

2.98

205-206 Ethanol

2.78

2.90

201

2.86

2.98

230-292 Ethanol

2.92

2.90

110-120 Ethanolpetroleumethe 140-145 Ethanol

4.87

4.77

2.02

2.58

2.16

2.16O

2.20

2.82

5.77

5.97

3.12

3.68

Methanol

Yellow needles Bright 201-203 Ethanol yellow needles 204-205 Ethanol Bright yellow needles Yellow 228-230 Methanol crystals Yellow 142 Ethanol crystals

Calc’d: C, 72.08; H, 6.05. Found: C, 72.02; H, 6.11. lised from alcohol; m.p. 195196”. This melting point is identical with that found for the hydrochloride of the material prepared by Wieland et al. (7), by the reaction of phosphorus trichloride on lobelanidine and reduction of the dichlorolobelan so formed. When palladium black was used as a catalyst, saturation of the side-chain only occurred.

Our thanks are due to Dr. E. Flint for assistance in the preparat,ion of 2,4substituted derivatives of piperidine, and to Mr. L. Berger for the preparation of the salts of l-methyl-2,6-di-(/3-p-methoxyphenethyl)piperidine.The microanalyses were performed by Dr. A. Steyermark of the Microchemical Division of these laboratories.


v

d .

52


I

545

546

JOHN LEE AND WERNER FREUDENBERG SUMMARY

1. Nine derivatives of 2 6-di(phenethyl)piperidine (norlobelan), including lobelan, have been synthesized by the reduction of the corresponding l-alkyl2 6-distyrylpyridinium p-toluenesulfonates. 2. Three derivatives of 2,4-di(phenethyl)piperidine and two derivatives of 1-methyl-2-phenethylpiperidine have been synthesized by an analogous method. 3. The compounds examined for spasmolytic activity showed powerful myotropic and neurotropic effects. NUTLEY,N. J. REFERENCES (1) BUTH,KULZ,AND ROSENMUND, Ber., 72, 19 (1939). K i i t ~ ROSENMUND, , et al., Ber., 72, 2161 (1939). (2) KULZAND ROSENMUND, Klin. Wochschr., 17,344 (1938). AND MUNROE, J . Am. Chem. SOC.,61,91 (1939). BLICKEAND ZIENTY, J. Am. (3) BLICKE Chem. Soc., 61, 93, 771, 774 (1939). J . Pharmacol., 71, 317 (1941). POPKIN, (4) LERMANN, J . Pharmacol., 71, 320 (1941). Arch. Pharm., 272, 811 (1934). (5) KINDLER, (6) German Patent Application R 87,420 IVa/l2q. (7) WIELAND, SCHBPF,AND HERMSEN, Ann., 444,60 (1925). (8) WIELAND,DRISHAUS, AND WENNER, Ann., 473, 102 (1929). (9) WINTERHALDER AND SCHEUING, Ann..,473,133 (1929). (10) SHAW,J . Chem. Soc., 126, 2363 (1924). (11) CLEM0 AND GOURLAY, J. Chem. SOC., 478 (1938).

PIPERIDINE DERIVATIVES. PART 1. LOBELAN AND RELATED

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