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Syntheses of Some Norcholanylisoquinoline Derivatives.

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312119
Norcholanylisoquinoline Derivatives
319
5 J. Mokry und 1. Kempis, Lloydia 27, 428 (1964).
6 G. Czira, J. Tamas, K. Zdkey und Cy. Kalaus, Org. Mass Spectrom. Im Druck.
7 A. Buzis, C k Herrison und G. Lavielle, C. R. Acad. Sci. Ser. C 283 763 (1976); und Privatmitteilungen
8 Gy. Kalaus, P. Cyory, L. Szabd und Cs. S z h t a y , Acta Chim. Acad. Sci. Hung. 96, 385 (1978).
9 E. Khpdty und L. Szporny, Arzneim. Forsch. 26, 1908 (1976).
10 C. S. Marvel und J. C. Cowan, J. Am. Chem. SOC.61, 3156 (1939).
11 F. Cramer und K. G. Girtner, Chem. Ber. 91, 704 (1958). Phosphorsaure-(a-carbomethoxyvinylester)-diethylester (2b) wurde nach Cramer und G i r t n a hagestellt. Ausb. 72 %; Schmp.:
134-136’ 4:’,
1.4330;IR (Film): 1740 (CO), 1640 (C=C) cm-l.
[Ph 9981
Arch. Pharm. (Weinheim) 312, 319 324 (1979)
Syntheses of Some Norcholanylisoquinoline Derivatives
Yechiel Colander, Eli Breuer* und Shalom Sarel*
Department of Pharmaceutical Chemistry, The Hebrew University School of Pharmacy, Jerusalem,
Israel, P.O.B. 1 2 065
Eingegangen am 8. Mai 1978
N-Phenethyl- and N-(2-(3’,4’dimethoxyphenyl)ethyl~amides5-8 of cholanic A d and 3a-acetoxycholanic acid were subjected t o the Bischler-Napieralski reaction to yield the respective 3’,4‘-dihydroisoquinolines, 9-12. Reaction of 5 also yielded N,N-bis(phenethy1)cholanamidine 13. The
3’,4’dihydroisoquinoIine 11 was converted to the tetrahydro derivative 1 4 and to the aromatic
compounds 15 and 16.
Synthese einiger Norcholanyl-Isochinolin-Derivate
Die N-Phenethyl- und N-2-(3’,4’-Dimethoxyphenyl)-ethylamide
5-8 der Cholan- und der 3aAcetoxycholansaure werden durch Bischler-Napieralski-Reaktionin die entsprechenden 3’,4’-Dihydroisochinoline 9-12 verwandelt. Die Umsetzung von 5 liefert zusatzlich das N,N’-Bisphenethylcholanamidin 13. Ein typisches 3’,4’-Dihydroisochinolin11 wird in das Tetrahydroderivat
14 und in die aromatischen Verbindungen 15 und 16 uberfuhrt.
Although numerous examples of isoquinoline derivatives possessing interc ting pharmacological activities are known’-3), only two are derivatives of steroids4 In these
derivatives the isoquinoline nucleus is substituted at position 1 by a 2- or 6- androstanyl moietyS* 6 ) .
320
Golander, Breuer und Sarel
Arch. Pharm.
This paper is concerned with the preparation of a novel series of isoquinoline derivatives featured by the attachment of the side chain of a bile acid to the isoquinoline
nucleus.
The syntheses were based on the Bischler-Napieralskireaction by which amides
5-8, generated from the respective acid chlorides 3 and 4, were cyclized to 3',4'-dihydroisoquinolines 9-12 (see Table 1). The cyclizations of amides 7 and 8 were accompanied by hydrolysis giving rise to the 3a-hydroxy derivatives 11-12. In the reaction of amide 5 two additional products were isolated beside the expected dihydroisoquinoline 9 . These were identified as cholanic acid (l), and N,N'-bis-phenethylcholanamidine 13. The latter was characterized by its analytical and spectroscopic
data, and identified by independent synthesis from cholanic acid and excess phenethylamine in the presence of phosphorus oxychloride. The formation of 13 can be
envisioned to involve the respective imidoyl chloride or imidoyl dichlorophosphate
as intermediate7) arising from 5, and its subsequent reaction with a second molecule
of 5. This reaction appears to compete effectively with the cyclization when the aromatic ring is not properly activated.
Table 1 : Experimental Conditions f o r Preparation of the 3',4'-Dihydroisoquinoline Derivatives
9-12
Starting amide
Quantity
(mmols)
Amide
Solvent (ml)
ml P o C l 3
Reaction
time
(h)
Dihydroisoquinoline
formed
Yield %
5
(0.86)
C6H6 (5)
1
2
9
30
6
(0.23)
C6H6 (2)
0.185
1
10
90
7
(4.5)
CH3CsHs (50) 7
1
11
35
8
(5.2)
CHzClz (90)
2
12
80
9.3
The double bond in 12 was easily reduced by sodium borohydride in methanol,
giving rise to an epimeric mixture of 1 ',2', 3',4'-tetrahydroisoquinolines, 14. Aromatization of 12 by means of palladium black or Pd/C 5 76 in xylene yielded, in addition
to the expected isoquinoline derivative 15, a minor product which was shown to be
the 23-keto- (or 1'-acyl-isoquinoline) derivative 16. Its structure was inferred from
its spectral properties.
Pharmacology. Amides 5 and 8, the hydrochloride salts of the isoquinoline derivatives 12, 14 and 15, and the amidine 13, were submitted for pharmacological general screening. The derivatives of 3',4'-dihydroisoquinoline 12 and the 1',2',3',4'-tetrahydroisoquinoline 14, were found to possess immunosuppressive activity in a "minimum effective dose" of 50 mg/kg, when given i.p. to mice, in a maximum dose of
50 mg/kg/day for 4 days.
312179
1 I < = II, X = O H
2 H = OCOCH,, X = OH
3
4
321
Norcholunylisoquinoline Derivatives
n =H , X =
C1
R = OCOCH,, x =
c1
p
~2~
H
10 R' = H, R2 = OCH,
11 R' = O H , R2 = H
12 R' = O H , R2 = OCH,
5 R = 11, X = NH(CH2)2C,H,
6 R = H , X = i"H(CH2)2C6H3(OMe)2
7 R = OCOCH,, x = K H ( C H ~ ) ~ C ~ I ~ S
8
r < = OCOCII,,
X = NH(CH2)2C,H,(OMe)2
One of the authors (Y.G.) gratefully acknowledges a generous grant by The National Council
for Research and Development of Israel during the early stages of this work.
Experimental Section
Meltingpoinfs: uncorr. NMR spectra: Jeol C-60-H High Resolution NMR Spectrometer (TMS).
in CDCl3 unless otherwise indicated. IR specrru: Perkin-Elmer Model 237 Grating Infrared Spectrophotometer. U V specrru: Unicam Ultraviolet Spectrophotometer Model Sp. 800A. [.lo:
Perkin-Elmer 141 Polarimeter.
322
Colander, Breuer und Sarel
Arch. Pharm.
Acid Chlorides 3 and 4 were prepared by heating a mixture of the corresponding acids 1 and
2 with excess of thionyl chloride in benzene at 50-60' for about 4 h. The benzene and excess
thionyl chloride evaporated t o give fairly pure 3 and 4, which were directly used for the preparation of amides 5-8.
Amides 5-8
Acid chloride 3 or 4 was dissolved in benzene, and two equivalents of the appropriate amine in
benzene solution were dropped into former solution. After addition of the amine the benzene
was evaporated from the filtrate. The resulting amides (about quantitative yields) were crystallized from the solvents listed in Table 2. Their mass-spectra showed a molecular ion, and typical
peaks appeared at 1540 and 1640 cm-' in the infrared spectra. The chemical shifts of l8CH3
hydrogens were in t h e range of 0.62-0.65 ppm, and 0.90-0.93 ppm for 19CH3 hydrogens.
Table 2: Physical Properiies of N-Phenethylcholanamide and 3'. 4'-Dihydroisoquinoline Derivatives
Cpd.
m.p.
C
'
Solvent
of
Recrystallization
Analyses
Calcd.
[ c ~ ] ~ e Formula
C
H
N
C1
C
Found
H
N C l
5
60-70
Methanol
Cj2H49NO
82.9
10.58
3.0
82.9
10.58
3.4
6
Methanol
CwH~jN03
78.0
10.13
2.7
77.6
9.80
2.6
7
83-93
oil
-
CwHslNOj
78.3
9.79
2.7
78.2
9.49
2.3
8
65-75
Methanol
C36HssNOs
74.4
9.47
2.4
74.3
9.55
2.6
9
213-219
Ethanol
-3OOb.c C32H47N
85.8
10.58
10
252a
Ethanol
-27Oa.c C34H~zClN02 75.4
9.60
2.6
6.6
75.2
9.60
2.6 6.8
11
235-237a
257-258a
Acetone
Ethanol
+ lloa*c C32H48ClNO
9.65
9.34
2.5
6.3
76.8
73.3
9.78
9.38
2.2 6.1
12
86.3 10.56
77.2
+ lloa,d C34H52ClN03 73.3
ahydrochloride; bfree base; Cin chloroform; din ethanol; eall rotations were measured in solutions with ~ 1 . 0
Y, 4'-Dihydroisoquinoline derivatives 9-12
Amides 5-8 were cyclodehydrated under reflux conditions as detailed in l a b l e 1. The solvent
and excess reagent were evaporated, in cases of products 10 and 12, the isolation of pure products
was accomplished by converting the crudc residues t o t h e hydrochloride salts with ethanolic HCI,
followed by crystallization. Compound 11 was isolated by separation on TLC preparative silica
gel plates (chloroform-acetone 8:2).The isolation of 9 will be described under the next title.
In addition t o the physical properties in Table 2, compounds 9-12 have been identified by
means of mass spectra (M+),vC=N at approximately 1650 cm- of t h e hydrochlorides, and by
their maxima in the ultraviolet a t about 243, 303 and 350 nm. The chemical shifts of l8-CH3
hydrogens was in average 0.65 ppm and 0.92 ppm for 19CH3 hydrogens.
Cyclodehydration of 5
The formation of N,N'-bis-phcnethyl cholanamidine 13 and 1-(24-norcholanyI)-3',4'-dihydroisoquinoline (9).
312179
Norcholanylisoquinoline Derivatives
323
0.4 g (0.86 mmol) of 5, and 1 ml phosphorus oxychloride were refluxed in benzene for two h.
After cooling and addition of dilute aqueous sodium hydroxyde, the products were extracted
with benzene, and benzene was dried and evaporated to yield 0.267 g of crude mixture. The least
polar product of the three main compounds obtained was the 3',4'dihydroisoquinoline 9, which
was separated from silica gel preparative TLC plates, using chloroform-acetone 8:2 as a developer.
The most polar product separated was cholanic acid (l), and the third product (30 % yield) was
found to be the amidine 13.
Alternative pathway for preparation of amidine 13
0.63 g Cholanic acid (1) and excess of phenethylamine (0.5 g) were refluxed in benzene solution,
in the presence of phosphorus oxychloride (1 ml) for 4 h. The amine salt precipitated during the
reaction. The reaction mixture was cooled, and the filtrate evaporated to dryness. The crude product was chromatographed on basic alumina, and the amidine 13 was collected, by elution with
chloroform-acetone (8:2). The crude amidine was converted into its hydrochloride salt and crystallized from acetone, m.p. 210-214'. [ a l =~ + 3' (CHC13); EIMS: m/e, 566 (M+); IR (KBr):
1660 (C=N) cm-1; 1H-NMR: (CCl4), 6 (pprn) = 0.58 (s. 3H, I8CH3), 0.89 (s. 3H, 19CH3), three
m for methylenes centered at 3.0, 3.39, and 3.80, 7.07-7.60 (m, 10H, aromatic).
l-(3a-hydroxy-24-norcholanyl)-6'~
7'-dimethoxytetrahydroisoquinoline
(14)
0.810 g (1.46 mmol) of 1 2 . HCI was dissolved in 15 ml methanol, and 0.20 g of sodium borohydride was added gradually while stirring and cooling. After two h the methanol was evaporated,
water and chloroform were added, and the product extracted into chloroform. The crude product
obtained after evaporation of the solvent was converted into its hydrochloride salt with ethanolic
HCI, and crystallized from ethylacetate-chloroform, m.p. 210-215'. TLC indicated that these
crystals are an epimeric mixture identified as the expected tetrahydroisoquinoline 14 (70 8 yield)
( a ] =~+ 30' (ethanol). EIMS: m/e 523 (M+); 1H-NMR: (CDC13) 6 (pprn) = 0.65 (s. 3H, 18-CH3),
0.90 (s. 3H, 19CH3), 4.52 (b.s. 2H), 3.13 (m. CH2-). 3.58 (m. CHI), 3.82 (s. 6H, OMe), 6.63
(b.s. 2H, arom.).
2-(3a-hydroxy-24-norcholanyl)-6',
7'-dimethoxyisoquinoline
(15 )
To a solution of 0.90 g (1.73 mmol) of 12 base in 15 ml xylene 0.90 g of palladium on charcoal
5 % was added. The mixture was refluxed for 30 h, cooled and immediately filtered. The filtrate
solvent was evaporated and the residue separated on tlc silica plates developed by chloroformmethanol 1 %. The main product (75 %) was the expected isoquinoline 15, crystallized (EtOH)
was the hydrochloride salt, m.p. 247-249'. (&ID = + 17' (ethanol). EIMS: m/e 519 (M+); IR
(KBr): 1630, 1610, 1605, 1510 cm-'; uv (ethanol) Amax ( E ) = 236 (23900), 265 (5200), 275
(4700), 285 (3700;, 298 (2800), 310 (3900). 323 nm (4500). 1H-NMR: (CCl4) 6 (pprn) = 0.67
(s. 3H, l8-CH3), 0.92 (s. 3H, 19CH3). The minor product isolated was less polar than 15. Its
spectral data indicates the existence of the ketonic structure 16. The hydrochloride salt melts
= + 16' (ethanol). EIMS m/e (rel. intensity) 533 (M, 34), 518 (M-CH3, 2),
at 213-2149
232 (32). 219 (29), 189 (base peak, 100); IR (KBr): 1700,1660,1555 and 1500 cm-1; uv (ethanol) hmax ( E ) = 254 (8900), 336 nm (3200); 1H-NMR: (CDCl3) 6 (pprn) = 0.78 (s. 3H, l8-CH3),
0.91 (5. 3H, 19-CH3), 1.01 [d (J=6 Hz), 3H, 21CH3], 1.69 (b.~.lH, OH), 3.27 [d (J=6 Hz, 2H,
H-221, 3.5-4.0 (b.lH, CHOH), 4.05 (s. 6H, OCH3), 7.06 (s. lH, H-5"), 7.44 [d (J=5 Hz), lH,
H-4'1, 8.45 [d (J=5 Hz), H,H-3'1.
3 24
Marsura, Taillandier und Boucherle
Arch. Pharm.
Literatur
1 P.D.Mooncy, B.A. Both, E.C. Moore, K.C. Agrawal, and A.C. Sartorelli, J. Med. Chem. 1 7 ,
1145 (1974).
2 R. Paul, J.A. Coppola,and E. Cohen, J. Med. Chem. 15,720 (1972).
3 P.N. Neenan, and I.B. Hillary, Lancet 2,614,641 (1969).
4 9-aza steroids and 13-am steroids may also be considered derivatives of isoquinoline: a) A.1.
Meyers, G.G. Munoz, W. Sobotka, and K. Baburao, Tetrahedron Lett. 1965, 255; b) G. Jones,
and J. Wood, Tetrahedron 21,2529 (1965); c) A.J. Birch, and G.S.R. Subba Rao, J. Chem.
SOC.1965, 3007; d ) S.U. Kcssar, M. Singh, and A. Kumar, Tetrahedron Lett. 1965, 3245.
5 A.K. Tokarev, L.N. Volovelskii, A.K. Sheinkman, and S.N. Baranov, Zh. Obshch. Khim. 42,
460 (1972).
6 L.N. Volvelskii, A.K. Sheinkman, M.Ya. Yakovlcva, and A.K. Tokarev, Zh. Obshch. Khim.
43, 1414 (1973); C.A., 79,6657 (1973).
7 L.A. Paquette, Principles of Modcrn Heterocyclic Chemistry. p. 282, W.A. Benjamin, Inc.,
New York - Amsterdam 1968.
[Ph 9993
Arch. Pharm. (Weinheim) 312, 324-331 (1979)
Synthesis and Stereochemistryof (3-Arylethenyla-Hydroxyalkyl Ketones
Alain Marsura, Georges Taillandier * and Andre Bouchcrle
Laboratoire de Chimic et Toxicologie, Groupe d’btude et de recherches du medicament, Universitb Scientifique et MCdicale de Grenoble; Avenue de Verdun, 38 240 Meylan (France)
Eingegangen am 8. Mai 1978
Some new Parylethenyl a-hydroxyalkyl ketones were prepared. Their U.V., I.R. and N.M.R.
data are given and their stereochemistry is discussed.
Synthese und Stereochemie von a-Hydroxy-dialkyl-aryliden-ketonen
Mehrere neue a-Hydroxy-dialkyl-aryliden-ketonewurden synthetisiert. Ihrc [J.V., I.R. und
N.M.K.-Charakteristika sind angegeben und lhre Stereochemie wird diskutiert.
In a former paper we reported that the oximes corresponding to the hydroxyketones
RR’C(OH)-COCH3 possess a neurotropic activity’). So we tried to synthesize the
hydroxyketones RR’C(OH)-CO-CH=CH-C6H4-R”. Our interest in these compounds
is both pharmacological, because of their resemblance to the former molecules, and
chemical, because of the numerous possible isomers.
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