PDF ., Studies in Potential Amoebicides: Part II - Synthesis of Some

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• .,

Studies in Potential Amoebicides:

Part II - Synthesis of Some Polymethylene Diamines

( Miss) S. MAHBOOB & M. L. DHAR Central Drug Research Institute, Lucknow ( M amlscfipt received, 6 Sept. 1954)

Some symmetric and some unsymmetrlc polymethylenediamines carryin~ a secondary and a tertiary or two tertiary nitrogen atoms with an Intervening brid~e of 3 and 9 car

bon atoms have been synthesized as possible amoebicidal a~ents.

I

N the absence of any knowledge of the precise physiology and metabolic r.re- ' quirements of Entamoeba 'histolytfea, leads for a search for newer amoebicidal agents may be obtained from' the possible mode of action of the therapeutically accept

ed drugs. One line of our approach to this problem, based on a possible mode of action of the halogenated-8-oxyquinolines, has been , described earlier1,2.

Emetine'' and conessines, the powerful systemically active amoebicidal agents, have the disadvantage of high toxicity5,6.

, Based on the assumption that somewhere in the structure of emetine must lie the clue to a useful amoebicidal drug7,8, several, attempts have been made to obtain compounds struc

turally related to emetinev-" and conessinew, , Both emetine and conessine are charac

, ..terized by the presence of two nitrogen , 'atoms in their respective molecules. The nitrogen atoms of emetine, of which one is ,secondary and the other tertiary, are sepa

'rated by a bridge of five carbon atoms, and in conessine the two tertiary nitrogen atoms are .' separated by a chain of nine (or elevens ) i,carbon atoms. Both these compounds are spatially aplaner, and this character would

tend to hinder their attachment to receptors in the biophase through the operation of van der Waal's forces. It would, therefore, seem that the nitrogen atoms in these two widely different compounds constitute the vital centres for their identical biological activity; the attachment to the bioreceptors occurring through the mediation of hydrogen bonds. The super-structures of these two com

pounds would appear to be only pharmaco

dynamically important and responsible also, perhaps, for their high toxicity.

Based on these assumptions it was con

sidered of interest to build the simplest analogs of emetine and conessine in a series of variously substituted polymethylene di

amines. Since the spatial shape and volume of the end groups would tend to be limiting factors in the approach of a drug molecule to the bioreceptor, close enough to permit hydrogen bonding, it was decided to restrict the choice of these groups, in the present syntheses, to open chain alkyl and aryl groups and to cyclic groups of small volume.

The relative charge potential of the substi

.tuents would materially influence hydrogen bonding and in a crowded reaction medium' like the biophase, it may be necessary that for optimal activity the electron density on the two nitrogen atoms must lie between certain limits. '

I-n-Propyl, n-butyl, n-hexyl, n-dodecyl and ~-:phenylethyl amino-3-diethylamino

propanes, 9-di-n-butylamino-l-n-propyl, n

butyl, iso-butyl, n-amyl, iso-amyl, n-hexyl,

t

,~ ^,

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J. SCI. INDUSTR. RES., VOL. 14B, 1955

n-heptyl, n-octyl, or iso-octyl, n-dodecyl, phenyl, o-anisyl, p-anisyl, benzyl and _~

phenylethyl nonanes and the corresponding 9-morpholino and piperidino compounds and 1: 9-diethyl, di-n-butyl, di-n-amyl, di-n

heptyl amino nonane diamines and 1: 9 dipiperidino and morpholino nonanes have now been synthesized. Attempts to prepare the corresponding pentamethylene diamines lead to cyclization and further work in this series will be reported later.

1-Alkyl-( or aryl )-amino-3-diethylamino

propanes were prepared by the condensation of 3-diethylamino-1-chloropropane hydrochlo

ride> with various alkyl and aryl primary amines, according to the method of Kermack et al.¹⁶, described for the preparation of 1-n

propylamino-2-diethylaminoethane. In the present work, however, the reaction mixtures were refluxed for 6-20 hr. against 2 hr. em

ployed by them.

1-Alkyl-(or aryll-amino-s-di-s-butylamino

nonanes were prepared by converting nona

methylene glycol into the corresponding chlorohydrin by a slight modification of Perrine's method'", and condensing the latter with di-n-butyl amine. This method did not, however, give homogeneous products in con

densations involving morpholine and piperi

dine. 9-Morpholino-1-nonanol and the cor

responding piperidino compound were pre

pared by refluxing nonamethylenechloro

hydrin with the appropriate base in the pre

sence of xylene or toluene. The correspond

ing chlorocompounds were prepared by re

fluxing the amino nonanols with thionyl chloride as detailed in the experimental.

The resulting 9-dibutylamino (piperidino and morpholino l-Lchlorononanes were. refluxed with various alkyl ( or aryl) primary amines for 30-40 hr., with or without a solvent ( xylene ). Condensation with low boiling amines was carried out in benzene solution

in a sealed tube at 100° for 60-70 hr. No.

solvent was, however. employed for con

densation with iso-butyl and iso-amyl amines.

1: 9-Ditertiary-aminononanes were pre

pared by heating nonamethylene dibromide with appropriate amines in xylene.

Most of the compounds now reported are hygroscopic and were freshly distilled before analysis.

The compounds are under test for their amoebicidal activity (in vitro and in vivo) in the Microbiology Division of this Institute and their results will be communicated separately.

Experimental procedure

1-~ -Phenylethylamino - 3 - diethylaminopro

pane - 3-Diethylamino'-f-chloropropane hy

drochloride (8,3 g.; 0·45 mol.) , ~-phenyl

ethylamine (12,1 g.; 1 mol.), potassium car

bonate ( 7 g.), and ethanol ( 30 cc.) were re

fluxed for 10 hr. Ethanol was distilled off and the reaction mixture diluted with water, made alkaline with sodium hydroxide (c. 10 per cent) solution and extracted with ben

zene. The benzene extract was dried over potassium carbonate, the solvent removed and the oil distilled; b.p. 144°/3 mm.; yield 7·5.g.; 72 per cent. (Found: N 12·0. Cl5H26N2 requires: N, 12·0 per cent.)

Various compounds prepared in this series are given in Table 1. •

N onamethylene chlorohydrin^{l 7}- Noname

thylene glycol (9,2 g.), hydrochloric acid ( 66·5 cc. d, 1-16 ) and water ( 20·5 cc.) were heated at 100° for 2 hr. The oily layer con

taining about 50 per cent of the chlorohydrin was separated and the aqueous layer was extracted with petroleum ether (b.p. 100°

110°) for 24 hr. in a liquid-liquid extractor at a bath temperature of 85°-90°.. Petro

leum ether was removed and the total oil

TABLE 1 (C,H,),N (CH~),NHR

SL. No. R B.P. YIELD

0/,. ^NITROGF.N

.

Found Required

% %

'56 57 58 59

n-CaR, n-C..H, n-C.H1::l n-~IH!I .

60°~62° /4 rnm.

82°/2 rnrn, 115°/4 mm, 170°-72°/3 mrn,

35 33 58 55

16-0 15·0 13'4 9·7

16·2 V\·O 13·1 9'4

60 •(CH,l,-Q 144°/3 mm, 72 12·0 12-0

·Uncorrected.

2

(3)

No on

nyl ire

ride are fore heir (vo) tute ated

lpro

~hy

enyl

car

e re

d off 'ater, c. 10 ben

over loved yield

{26

N2

series lame

acid were r con

iydrin r was , 100°·

ractor Petro

tal oil

----.

uired l·~

lJ'2 :',0

3·19·4

Z',O

MAHBooB & DHAR: STUDIES IN poTENTIAL AMOEBIcIDES: PART II

•

distilled in vacuum; b.p. 132°/5 mm.; yield 9·8 g.; 96 per cent.

9- M orpholino-t-nonanol-s- Nonamethylene chlorohydrin (55 g.; 1 mol.) , morpholine ( 100 g.; 3·66 mol.) were refluxed in xylene ( 150 cc.) for 30 hr., b.p. 185°/7 mm.; yield 57 g.; 88 per cent. This compound has been prepared earlier by Pollard et al.^1S•

9-Piperidino-l-nonanol (Sl. No. 61)

Nonamethylene chlorohydrin (33 g.; 1·9 mol.) , piperidine ( 63 g.; 7·5 mol.), and dry toluene (100 cc.) were refluxed for 40 hr. The mixture was allowed to cool, diluted with water, and shaken with 200 cc. of sodium hy

droxide solution (5 per cent). The xylene layer was separated and the aqueous layer extracted with benzene. The combined xylene solution and benzene extracts were dried over potassium carbonate, the solvent removed and the oil distilled; b.p. 157°-59°/

4 mm.:yield 37 g.; 86 per cent; n',;' =1,4704., (Found: N, 6·3. C_14H29NO requires: N, 6·2 per cent.) ,

9-Morpholino-l-chlorononane (st. No. 62)

Thionyl chloride (17 cc.), in dry chloro

form (17 cc.) was added slowly to a well-

cooled solution of 9-morpholino-l-nonanol ( 24 g.; 0·1 mol.) in chloroform ( 24 cc.). The mixture was heated on a water bath for 2 hr., allowed to cool to room temperature and poured over ice. The aqueous layer was removed and the chloroform layer shaken with sodium hydroxide solution ( 5 per cent ), washed with water, dried over potassium carbonate and distilled; b.p. 153°-55°/3 mm.;

yield 20 g. ; 80 per cent; n

'0'

= 1-4665. ( Found:

N, 5·9. C13H26CINO requires: N, 5·7 per cent.) 9-Piperidino-l-chlorononane (Sl. No. 63) was prepared by the above method; b.p, 137°_40°/3 mm.; yield 95 per cent; n'o9=

1·4657. (Found: N, 5·6. C_14H2sNCI requires:

N, 5·7 per cent.)

1-n - Dodecylamino -9-di- n - butylaminonon

anewas prepared by condensing 9-di-n-butyl

amino-l-chlorononane ( 3·8 g.; 1·3 mol.) and dodecylamine (6,4 g.; 3·5 mol.) at 140°_60°

for 30 hr.; b.p. 236°/3 mm.; yield 3·5 g.; 60 per cent. (Found: C, 78·9; H, 14·2; N,6·4.

C29H62N2 requires: C, 79·3; H, 14'2; N, 6·4 per cent.)

1- Benzylamino - 9 - di - n - butylaminononane was prepared by heating 9-di-n-butylamino-

TABLE 2 (,,·Bu),N(CH,),NHR

sc, No. R B.P.- . REF. INDEX Y1ELD NITROGE.N

01 ,0

Found Required

0'/0 %

64 ^1l--C3H, 165'/4 ^unu. D~fi,j =1'462U 90 o·~ 8,9

65 n-C.Ht 175'/4 ^nun. ^2U ^8·5 s-a

Gil Iso-CcH. 177°/3 IllIII. n~7=1'4481 59 8·8 8'5

67 n-C,H 11 17G'/3 ^111111. no ^:HI=1'4610 40 8·4 ^8'Z

68 Iso-C/iH n lS5'f;J ^unu, Jl~li',j =i --1-182

-

₅₀ _8·3 8',Z

60 1£·C.Hu It;jOI~' ~ JIlUl. 50 8'0 7'9

~ c -5

70 II.-C7H l: i 212°/:i nnu, no ^~1'4534 4U ^7·2 7'6.

71 ,..-C.Hl1 20:l°/3 unu, D~6'.) =1.4576 33 7'4 7·3

72 1J-C1:H:lli 236°/3 unn. 60 6'4 6'4

1~5°/;j mill.

73 -0 no'7 =1'5149 36 8'3 8'1

OCH.

74

-0

215°/2 lim. 70 7·2 7·4

75 OOCH, 230°/3 ^unn, n~8'5.=1·5035 80 7'2 7'4

76

-CH:!-<.J

^192°/3^mm, ^_n~···=1·4Q08 54 8'0 7'&

77 -(CH,),-D 194°/3 mm. n~T=1'5118 50 7'0 7·4

·Uncorrected.

3

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j.

sci.

IN':btSTR. RES., VOt. 14B. 1955 l-chlorononane (3,7 g.; 1·3 mol.) and benzyl

amine ( 18 g.; 19 mol.) at 140°_60° for 30 hr.:

b.p, 192°j3 mm.: yield 2·6 g.; 54 per cent;

n~···= 1·4908. ( Found: C, 80·1; H, 11·8; N.

8·0. C24HuN~ requires: C, 80·1; H, 12·2;

N. 7·8 per cent.)

1-0-A nisidino-9-di-n-butylaminononane was prepared by refluxing 9-di-n-butylamino

l-chlorononane (2·7 g.; 1 mot), s-anisidine ( 5 g.; 4 mol.] and xylene (25 cc.) for 37 hr.;

b.p. 215°/2 mm.; yield 2·4 g.; 70 per cent.

(Found: C, 76'7; H, 11·9; N, 7·5. C24HuNzO requires: C, 76·5; H, 11·8; N, 7·4 per cent.)

All compounds prepared in this series are recorded in Table 2.

9 - Morpholino -1-n - butylaminononane was prepared by heating 9-morpholino-1-chloro

nonane (4,5 g.; 1·8 mol.) , n-butylamine (7'3 g.; 10 mol.) and benzene ( 15 cc.) in a sealed tube at 100° for 73 hr.; b.p. 175°/3 mm.; yield 5·1 g.; 84 per cent; n~8··=1·4621.

(Found: C, 71'7; H, 13·0; N, 10·1. C_{16H MN}_IIO requires: C, 71'8; H, 12·8 ;N, 9·9?er cent.)

9- Morpholino-l-n-hexylaminon"dnane was prepared by heating 9-morpholino-l-chloro

nonane (3 g.; 1·2 mol.), n-hexylamine (4'8 g.;

4·8 mol.) at 140°-60° for 40 hr.; b.p. 180°/3 mm.; yield 2·6 g.; 72 per cent; n~"=1·4609.

(Found: C, 72·2; H, 13-0; N, 9·2. CllH 40N 20

requires: C, 73'0; H, 12·9; N, 9·0 per cent.) All the compounds prepared in this series are given in Table 3.

9 - Piperidino -1- n - heptylaminononane was prepared by refluxing 9-piperidino-l-chloro

nonane (2,5 g.; 1 mol.) , n-heptylarnine (5 g.; 4·5 mol.) and xylene (25 cc.) for 36 hr.;

b.p, 177°/3 mm.; yield 1·1 g.; 34 per cent;

n'o'=1·4691. (Found: C, 77·2; H, 13·6; N, 8·2.

C_nH_44NjIrequires: C, 77·7; H, 13·6; N, 8·6 per cent.)

9 - Piperidino - 1- iso - octylaminononone was prepared by refiuxing 9-piperidino-l-chloro

nonane (2,5 g.; 1 mol.) iso-octyl-amine ( 5·1 g.; 4 mol.) and xylene ( 25 cc.) for 36 hr.:

b.p. 210°/5 mm.: yield 3 g.; 90 per cent;

n~···=J-4581. (Found:. C, 77·3; H, 13·8;

N, 8·1. CZIIH46NII requires: C, 78·0; H, 13·7;

N, 8·3 per cent.]

All the compounds prepared in this series are recorded in Table 4.

TABLE 3

QIi-(CH,l,NHR

SL. No. R B.P. REF. INDEX YIELD

%

NITROGEN

~---.

Found Requ~ed

% %

78 n-C,H, 1~5"/3 mm, n~' =1'4662 8~ 10·6 10'4

79 ,,·C,H. 1711"/ol mm, 1l~lii.5 =1'4621 84 10'1 9'9

80 Iso-C,H. 166"·70"/3 com. n~8" =1'4~72 ~1 10·0 9'9

81 ....

'II-C.Ru 175°/3 rom. no ^'~9=1,4615

.

⁸⁴ ^9,6 ^9'4

82 Iso ..C_1Hl1 183°.86"i4 mm, n~8'li =1'4-590 70 9'6 9'4

83 ,.·C,Hn 180'/3 mw. no ^H =l'J609 72 9·2 9'0

84 n-C,HlI :H2°}5 unu. n~G·5dl'461.9 90 8'6 8'6

85 Iso-C,H" 193'·95'/3 rum, ni', =1'4601 ^"8 53 8·3 8'2

86 "·c.,H,, 245'/3 mm, 80 6'9 7'1

87 -0 212"/2 turn. D~1 =1,5240 70 0·4 9'2

OCH.

88

-o

^223°/2^mID. D~8'5 =1.5227 80 8,5 8'4

811 o-0CH. 235°/4 mm, n;'=1'5241 _ 0 8·6 8'4

90 .CH.-D 215"/! mm, n~· =1,5081 50' 8·8 8·8

91 •(CH,).-Q 22-1°/3 mw . n~7 -1'5143 80 8'4 8'4

eUnccrrected,

4

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~'8 g.;

180°(3 .,4609.

[40N20 cent.) series ne was cnloro

lamine 36hr.;

r cent;

N,8·2.

N,8'6 me was -chloro

l-amine . 36 hr.;

:r cent;

, 13·8;

1,13-7;

is series

Required

%

10·4 9·9 9·9 9·4 9·4 9'0 8·6 S'2, 7·1

MAHBOOB & DHAR: STUDIES IN POTENTIAL AMOEBIC IDES : PART II

•

TABLE"

0-

^(CH,J,NHR

S, No. R B.P. REF. INDEX

102 101 92 93 94 95 96 97 98 99 100

OCH,

-0

II·C,H, II·C.H, Iso·C.H, II-C.Hu Iso·C.H11

..·C.Hl I

"·C,H,, Iso-C,H"

II·C"H..

172°/6 mm.

173°/3 mm.

167°/3'5 mm.

178°.82°/2'5 mm.

172°/3.5 mm.

192°/4'5 mm.

177°/3 mm.

192°/4 mm.

207°.12°/3 mm,

n~'^=1,4685

n~'=1'4691 n;"'=1'4581

n~B^=1'5322

103 o-0CH.

104 .CH,~

105 -(CH,l,-Q

- Uncorrected.

Y,ELD

%

64 78 79 64 94 51 34 90 46 53

30

25 70

80

NITROGEN , Found Required \

% %

10'3 10'0 9'6 9'5 9·4 9·1 8·2 8'1 6'9

9·3

8'6

8'0 8'4

8'6 8'8

8·5

S'- No.

106 107 108 109 110 111"

R

(C,R.l,N

(...C.H,l,N

(II-C.H11J.N·

(II-C,HlIl,N·

o·

0

TABL E 5 R(CH,l,R

B.P. REP. INDEX

142°.44°/4 mm. n~"~=1'4448 192°/3'5 mm. _n~'=1,4471 22(;°/2'5 mm. n~'=1'4501 225°.30°/10" mm. n;"=1'4540

n~""=1'4772

·Uncorrected.

YIELD

%

67 72 70 63 76 75

NITROGEN·

Found

% ^Required%

10·7 10'4

7'8 7·3

6'7 6'4

5'6 5·1

9'7 9'8

9·2

1: 9-Di-n-butylaminononane was prepared by refluxing nonamethylenedibromide (2'8

and xylene (25 cc.) for 24 hr.; b.p. 225°

30°/10-4 rom. (bath temperature); yield 3·5 g.; 1 rnol.), di-n-butylamine ( 8·4 g.; 6·5 mol.) g.; 63 per cent; n;" = 1·4540. (Found: C, 80'7;

and xylene (25 cc.) for 24 hr.: b.p. 192°/3.5 H, 14·7; N, 5·6. CS7H7SN2 requires: C, 80·6;

s·,

rnm.: yield 2·8 g.; 72 per cent; n;'=1·4471. H, 14·3; N, 5·1 per cent.)

(Found: C, 78'8; H, 14·2; N, 7'8. C25H54N2 Compounds in this series are given in

8'S requires: C, 78'4; H, 14·2; N, 7·3 per . cent.)

1: 9-Di-n-heptylaminonona1te was obtained Acknowledgement Table 5.

by refluxing nonamethylene dibromide (2'8 Our thanks are due to Mr. ]. Saran for g.; 1 mol.), di-n-heptylamine ( 8·4 g.; 4 mol.) microanalyses.

5

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J.

SCt. tNDUSTR. RES., VOL. 14B, 1955

References

1. GOP.~LCHARI. R.. POl'L1, S. P., ANAND, N. &

DHAR, M. L., ]. sci. industr. ses., 13B ( 1954 ), 15.

2. IYER. R. N., ANAND, N. & DHAR, M. L., ]. sci.

indus/r. Res., 13B (1954). 451.

3. OPENSHAW. H. T. & WOOD, H. C., J. chem, s«;

( 1952). 391.

4. HAWORTH, R. D., MCKENNA, J., POWEI,L, R. G. & WHITFIELD, G. H., Chem. (;. Ind:, ( 1952). 215.

5. KLATSKIN, G. & FRIEDMAN, H., Ann. Tnst, Med., 28 ( 1948 ). 892.

6. CROSNIER, R., DARBON, A., DUCOURNAU. P. &

COSTEROUSSE, L., Bull. Soc. Path. esot., 45 ( 1952). No. 1, 86; d. Trop. Dis. Bull., 49 ( 1952 ). 863.

7. BATTERSBY; A. & OPENSHAW,H. T., J. chem, Soc .• (1949),3207.·

8. PAlLER, M. & PERSCHINSKI. K.,

u».

^Chcm.,80 (1949),94.

9. PYMAN, F., cu«. (;. ie«, IS ( 1937 ), 789.

10. GOODWIN, L., HOARE. C. & SHARP, T., Brit. ].

Pharmaool., 3 (1948),44. . 11. GOODSON, J., GOODWIN, L., GORVIN, J. H.,

Goss, M. D .• KIRBY, K. 5.. LOCK. J. A., NEAL, R. A., SHARP, T. M. & SOLOMON, W., Brit. J.

Pharmacol., 3 (1948). 49. 62.

12. OSBOND, J. M., J. chem. Soc., (1951), 3464;

(1952),4785.

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1956. .

14. DODGSON, D. P. & HAWORTH. R. D .• J. chem, Soc., (1952),67.

15. MUNCH, R., THANNHAUSER, G. T. & COTTLE.

D. L., J. Amer. chem. Soc., 68 (1946),1297.

16. KERMACK, W. O. & WIGHT, T. W., J. them, Soc., ( 1953 ), 1421.

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chem, Soc., 61 ( 1939 ), 3440.

Synthetic Experiments In the Benzopyrene Series: Part LII

Constitution of Acrammerin

S. K BALASUBRAMANIAN. S. NEELAKANT AN &

T. R. SESHADRI

Department of Chemistry, University of Delhi, Delhi ( Manuscript received, 18 July 1954)

Acrammerin pentamethyl ether has been found to be different from 5: 7: 8: 3' : 4': 5'

hexamethoxy flavone prepared earlier by Rao et al.³usin~ the method of nuclear oxidation and now by the diketone method. The possi

bility of its being the isomeric 5 : 6 : 7 : 3': 4' : 5'-hexamethoxy flavone has also been tested and eliminated by comparison with authentic samples prepared by the earlier method of Rao et at. and again now by the diketone method. The hexahydro"y ftavones and their partial methyl ethers are described.

A

CRAMME RI N, isolated by GaIlokidze and Kutidze! from the pods oi Gleditsia iriacanthos, was found to have the molecular formula C16H120S and a methoxyl group. On acetylation and methylation it gave a penta-acetate (m.p. 231°-32°) and a pentamethyl ether (m.p. 254°.56°) respect

ively thereby showing that it contained five hydroxyl groups. Fusion of acrammerin pentamethyl ether with potash gave tri

methyl gallic acid, trimethyl pyrogallol and 1: 2: 5-trimethoxy-3-hydroxy benzene.

When acrammerin itself was fused with potash, acetic acid, pyrogallol, gallic acid and 2: 4: 6-trihydroxy anisole were obtained.

Based on these degradations, it was given the'

constitution 5: 7: 3': 4': 5'-pentahydroxy-8

methoxy flavone (I).

Ho

C(x)-Q.'OH 0

_I _H

Ho C OH

o ,( I

Gakhokidze" reported the synthesis of 5: 7: 8: 3': 4': 5'-hexamethoxy flavone (II) and the hexahydroxy flavone. 2: 4-Di

6