Synthesis of 3-alkyl- and 3,9-dialkyl-1,2,3,4-tetrahydro-γ-carbolines

Full text of DOI:10.1023/A:1014003010986

Pharmaceutical Chemistry Journal
Vol. 35, No. 9, 2001
DRUG SYNTHESIS METHODS
AND MANUFACTURING TECHNOLOGY
SYNTHESIS OF 3-ALKYL- AND 3,9-DIALKYL-
1,2,3,4-TETRAHYDRO-g-CARBOLINES
N. N. Smolyar,1 A. S. Volchkov,1 and Yu. M. Yutilov1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 9, pp. 46 – 48, September, 2001.
Original article submitted March 13, 2001.
R
The derivatives of tetrahydro-g-carbolines exhibit a bro-
N
N
ad spectrum of pharmacological properties [1]. Examples of
N
H
N
highly effective drugs widely used in medicine are offered by
3-methyl-9-benzyl-1,2,3,4-tetrahydro-g-carboline naphthale-
ne-1,5-disulfonate (diazoline) [2] and 9-[2-(2-methylpy-
rid-5-yl)ethyl]-3,6-dimethyl-1,2,3,4-tetrahydro-g-carboline
dihydrochloride (dimebone) [3].
50% KOH
–
I
IIIà, IIIb
R'X
RX
–
X
X
R
R
N
+
N
+
N
Tetrahydro-g-carbolines are usually synthesized by the
Fischer method employing the condensation of phenylhydra-
zine derivatives with N-methyl-g-piperidone [4]. The resul-
ting 3-methyl-1,2,3,4-tetrahydro-g-carbolines are used as in-
termediate compounds in the synthesis of biologically active
substances [5].
Using g-carboline as the initial compound, we planned to
obtain a series of N-alkyl(benzyl)tetrahydro derivatives from
monoquaternary salts by analogy with the synthesis of subs-
tituted spinaceamine and 2-azaspinaceamine [6, 7] and pyri-
dyl-N-alkyltetrahydroharmines [8].
N
H
IVà –IVf
NaBH4
'
R
IIa – IId
NaBH4
R
R
N
N
N
N
H
'
VIà –VIf
R
Va – Vd
II, III, V, R = CH3 (a); R = C6H5CH2 (b); R = CH2CH2OH (c);
S
R =
(d)
N
Cl
The initial g-carboline (I) was synthesized using the Gra-
ebe – Ullmann reaction proceeding from 1-phenyl-1,2,3-tria-
zolo[4,5-c]pyridine [9]. The reactions of compound I with al-
kyl halides yielded monoquaternary salts (IIa – IId), which
were reduced by sodium borohydride to obtain 3-alkyl(ary-
lalkyl)-1,2,3,4-tetrahydro-g-carbolines (Va – Vd) with a yield
of 60 – 91% (Table 1).
The proposed structures of quaternary salts IIa – IId and
the corresponding reduction products Va – Vd were confir-
med by the 1H NMR data (Tables 2 and 3). For example, the
reduction of 3-methyl-g-carbolinium iodide IIa [10] leads to
3-methyl 1,2,3,4-tetrahydro-g-carboline (Va), previously
synthesized by the Fischer method [11, 12].
COCH2CH2
IV, VI, R = R' = CH3 (a); R = CH3, R' = CH2CH2OH (b); R = CH3,
S
R' =
(c)
N
Cl
COCH2CH2
R = CH2C6H5, R' = CH3 (d); R = R' = CH2C6H5 (å);
R = CH2C6H5, R' =CH2CH2OH (f)
X = I (IIa, IVà, IVd); Cl (IIb –IId, IVb, IVc, IVe, IVl)
In the 1H NMR spectrum of salt IIa, the signals from py-
ridine protons H-1, H-2, and H-4 are observed in the region
of aromatic shifts. In contrast, the 1H NMR spectrum of com-
pound Va displays three groups of signals due to methylene
protons in positions 1, 2, 4 (Tables 2 and 3).
1
Litvinenko Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, Kiev, Ukraine.
514
0091-150X/01/3509-0514$25.00 © 2001 Plenum Publishing Corporation

Synthesis of 3-Alkyl- and 3,9-Dialkyl-1,2,3,4-tetrahydro-g-carbolines
515
washed with 5 ml of cold water, and recrystallized from
2-propanol to obtain 0.65 g (93%) of compound IIIa; m.p.,
79 – 81°C; C12H10N2; 1H NMR spectrum in CDCl3 (d, ppm):
3.82 (s, 3H, –N–CH3), 7.24 – 7.61 (m, 4H, arom. H-5…H-8),
7.89 – 8.04 (m, 3H, arom. H-1, H-2, H-4).
3-Benzyl-g-carboline (IIIb). Compound IIIb was obtai-
ned similarly to IIIa, proceeding from 3-benzyl-g-carbolini-
um iodide (IIb). After recrystallization from 2-propanol, the
yield of compound IIIa is 71%; m.p., 85 – 87°C; C18H14N2;
1H NMR spectrum in CDCl3 (d, ppm): 5.26 (s, 3H,
–N–CH3), 7.11 – 7.57 (m, 4H, arom. H-5...H-8), 7.48 (s, 5H,
C6H5), 7.90 (d, 1H, J 8.0 Hz, H-1), 7.98 (d, 1H, J 8.0 Hz,
H-2), 8.36 (s, 1H, H-4).
3-Alkyl-1,2,3,4-tetrahydro-g-carbolines (Va – Vd) and
3,9-dialkyl-1,2,3,4-tetrahydro-g-carbolines (VIa – VId). To
a solution of 5 mmole of a quaternary salt (IIa – IId,
IVa – IVf) in 50 ml of a 70% aqueous ethanol solution was
added at room temperature with intensive stirring by portions
(over 0.5 – 1 h) 10 mmole of sodium borohydride. When the
latter solution was completely added, the stirring was termi-
nated and the mixture was allowed to stand for 16 – 20 h.
Then the solvent was evaporated at a reduced pressure (wa-
ter-jet pump) and the residue was extracted with benzene.
The extract was dried over anhydrous alkali, the solvent was
distilled off, and the product was recrystallized from an ap-
propriate solvent (Table 1).
As is known, the interaction of 3-methyl-g-carbolinium
iodide IIa [10] with a concentrated alkali solution leads to the
formation of an anhydrobase possessing the structure of
compound IIIa [13]. Under analogous conditions, 3-ben-
zyl-g-carboliniumiodide IIb [10] yielded anhydrobase IIIb,
with the structure confirmed by the 1H NMR data.
Heating compound IIIa with methyl iodide in an alcohol
medium leads to a high yield of quaternary salt IVa, which is
reduced by sodium borohydride to 3,9-dimethyl 1,2,3,4-tet-
rahydro-g-carboline (VIa). By the same token, the reduction
of quaternary salts IVb – IVf led to tetrahydrobases
VIb – VIf (Table 1). The proposed structures of salts
IVa – IVf and the corresponding reduction products
VIa – VIf correspond to the observed 1H NMR spectra (Tab-
les 2 and 3). For example, the spectrum of compound VIa
displays, in comparison with the spectrum of the initial salt
IVa, additional signals from protons of the methylene groups
1-CH2, 2-CH2, and 4-CH2.
As is known, the group of 10-aminoalkyl derivatives of
phenothiazine contains a number of highly effective drugs
[14, 15]. With a view to study the pharmacological activity
of these compounds, we have synthesized with good yields
the derivatives of 1,2,3,4-tetrahydro-g-carboline (Vd, VIc)
containing nitrogen atoms of the pyrrole and tetrahydropyri-
dine fragments bound to 2-chlorophenothiazine.
Thus, we have developed a new approach to the synthe-
sis of 1,2,3,4-tetrahydro-g-carboline derivatives which al-
lows compounds with various alkyl and arylalkyl substitu-
ents at nitrogen atoms of both pyrrole and tetrahydropyridine
fragments.
TABLE 1. Yields and Physicochemical Characteristics of 3-Alkyl-
and 3,9-Dialkyl-1,2,3,4-tetrahydro-g-carbolinium Halides (IIa – IId,
IVa – IVf) and Their Reduction Products (Va – Vd, VIa – VIf)
EXPERIMENTAL PART
Target Initial
Yield,
%
M.p., °C (solvent
for crystallization)
Empirical
formula
com-
com-
The course of reactions was monitored and the purity of
products was checked by TLC on Silufol UV-254 plates elu-
ted in ethanol and developed by exposure to iodine vapors or
UV radiation. The data of elemental analyses of the products
agree with the results of analytical calculations according to
the empirical formulas. The yields and melting temperatures
of the synthesized compounds are listed in Table 1.
pound pound
IIa
I
92
86
81
98
88
97
64
90
89
95
91
88
82
60
86
50
65
78
83
79
232 – 234 (ethanol)
C12H11IN2
IIb
I
205 – 208 (2-propanol) C18H15CIN2
237 – 240 (2-propanol) C13H13CIN2O
245 – 248 (2-propanol) C26H19Cl2N3OS
305 – 308 (2-propanol) C13H13IN2
260 – 263 (2-propanol) C14H15CIN2O
230 – 233 (2-propanol) C27H21Cl2N3OS
202 – 204 (2-propanol) C19H17IN2
238 – 241 (2-propanol) C25H21CIN2
IIc
I
IId
I
IVa
IVb
IVc
IVd
IVe
IVf
Va
IIIa
IIIa
IIIa
IIIb
IIIb
IIIb
IIa
IIb
IIc
IId
IVa
IVb
IVc
IVd
IVe
IVf
The 1H NMR spectra were measured on a Tesla BS-467C
spectrometer (working frequency, 60 MHz; solvent, trifluo-
roacetic acid) and Varian Gemini-200 spectrometer (200
MHz; deuterated methanol and chloroform).
General method for the synthesis of quaternary salts
(IIa – IId). A mixture of 10 mmole of base I or IIIa, IIIb and
15 mmole of the corresponding alkyl halide in 15 ml of
2-propanol is heated to boiling for 3 – 3.5 h. Then the excess
alkyl halide and solvent are distilled off at a reduced pressure
(water-jet pump) and the quaternary salt residue was recrys-
tallized from an appropriate solvent (Table 1).
> 250 (ethanol)
C20H19CIN2
C12H14N2
168 – 169 (heptane)
158 – 160 (heptane)
49 – 50 (hexane)
73 – 74 (benzene)
69 – 70 (hexane)
71 – 72 (benzene)
88 – 89 (heptane)
89 – 90 (hexane)
145 – 147(benzene)
47 – 49 (benzene)
Vb
C18H18N2
Vc
C13H16N2
Vd
C26H22CIN3OS
C13H16N2
VIa
VIb
VIc
VId
VIe
VIf
C14H18N2O
C27H24CIN3OS
C19H20N2
3-Methyl-g-carboline (IIIa). To 1.2 g (4.0 mmole) of
3-methyl-g-carbolinium iodide (IIa) dissolved in 20 ml of hot
water was added 20 ml of a 50% aqueous KOH solution. The
precipitated light-yellow product was separated by filtration,
C25H24N2
C20H22N2O

516
N. N. Smolyar et al.
TABLE 2. 1H NMR Spectra of 3-Alkyl- and 3,9-Dialkyl-1,2,3,4-tetrahydro-g-carbolinium Halides (IIa – IId, IVa – IVf)*
1H NMR spectrum (CD3OD): d, ppm (J, Hz)
Com-
H1, d
H2, d
H4, s
N3-R
N9-R¢
H5, H6, H7, H8
pound
IIa
8.36, J 7.0 8.57, J 7.0 9.64
4.47 (s, 3H, CH3)
–
7.38 – 7.49 (m, 2H, H6, H7)
7.79 (d, 1H, H8, J 4.2 )
7.94 (d, 1H, H5, J 7.0 )
IIb
IIc
6.81, J 7.0 7.87, J 7.0 9.82 5.88 (s, 2H, CH2); 7.47 – 7.68 m, (C6H5)
–
–
7.47 – 7.68, m, H arom.
7.06 – 7.91, m, H arom.
7.53, J 7.0 8.06, J 7.0 8.92
4.06 (t, 2H, b-CH2); 4.51
(t, 2H, a-CH2)
IId
8.14, J 7.0 8.53, J 7.0 9.64
–
7.14 – 7.86, m, H arom.
3.80 (t, 2H, b-CH2); 4.95 (t, 2H, a-CH2);
7.14 – 7.86 (m, 4H, C6H4);
7.92 (d, 1H, H4, J 7.0 ); 8.32 (d, 1H, H3,
J 7.0 ); 8.59 (s, 1H, H1)
IVa
8.41, J 7.0 8.64, J 7.0 9.66 4.48 (s, 3H, CH3)
4.14 (s, 3H, CH3)
7.62 (d, 1H, H8, J 7.0 )
7.86 (d, 2H, H7, H8, J 7.0)
8.10 (d, 1H, H5, J 7.0 )
7.52 – 8.2, m, H arom.
IVb
IVc
8.37, J 7.4 8.60, J 7.4 9.62 4.45 (s, 3H, CH3)
8.27, J 7.0 8.68, J 7.0 9.67 4.51 (s, 3H, CH3)
4.04 (t, 2H, b-CH2)
4.71 (t, 2H, a-CH2)
7.61 – 7.2, m, H arom.
3.39 (t, 2H, b CH3); 4.96
(t, 4H, a-CH2 b-CH2); 7.61 – 7.92
(m, 4H, C6H4); 8.00 (d, 1H, H4,
J 7.2 ); 8.44 (d, 1H, H3,
J 7.2 ); 8.60 (s, 1H, H1)
IVd
IVe
7.43, J 7.0 8.12, J 7.0 9.01 5.37 (s, 2H, CH2); 7.04 (s, 5H, C6H5)
7.51, J 7.0 8.06, J 7.0 8.96 5.37 (s, 2H, CH2); 7.06 (s, 5H, C6H5)
3.58 (s, 3H, CH3)
7.18 – 7.97, m, H arom.
7.33 – 7.91, m, H arom.
5.37 (s, 2H, CH2);
7.06 (s, 5H, C6H5)
IVf
8.39, J 7.0 8.71, J 7.0 9.84 5.84 (s, 2H, CH2); 7.46 – 7.58 (m, 5H,
C6H5)
7.74 – 7.99, m, H arom.
4.05 (t, 2H, b-CH2); 4.71 t
(2H, a-CH2)
* Compounds IIc and IVd were dissolved in CF3COOH.
TABLE 3. 1H NMR Spectra of 1,2,3,4-Tetrahydro-g-carbolines (Va – Vd, VIa – VIf)
1H NMR spectrum (CDCl3): d, ppm (J, Hz)
Com-
N3-R
N9-R¢
H5, H6, H7, H8
pound
1-CH2 2-CH2 4-CH2
Va
2.82 t 2.82 t 3.72 s 2.60 (s, 3H, CH3)
H
H
H
H
7.07 – 7.44 (m,
H arom.)
Vb
Vc
Vd
2.85 t 2.85 t 3.72 s 3.79 (s, 2H, CH2)
7.23 – 7.43 (m,
H arom.)
7.03 – 7.09 (m, 5H, C6H5)
2.73 t 2.73 t 3.63 s
2.96 t 2.72 t 3.74 t
7.06 – 7.29 (m,
H arom.)
2.68 (t, 2H, b-CH2); 3.71 (t, 2H, a-CH2)
6.57 – 7.52 (m,
H arom.)
5.24 (s, 2H, b-CH2); 6.06 (t, 2H, a-CH2);
6.57 – 7.52 (m, 4H, C6H4); 8.32 (d, 1H, H4,
J 7.0), 8.56 (d, 1H, H3, J 7.0); 9.65 (s, 1H, H1)
VIa
VIb
VIc
2.89 t 2.89 t 3.75 t 2.60 (s, 3H, CH3)
2.76 t 2.76 t 3.60 s 2.51 (s, 3H, CH3)
2.93 t 2.93 t 3.72 s 2.68 (s, 3H, CH3)
3.63 (s, 3H, CH3)
7.00 – 7.46 (m,
H arom.)
7.09 – 7.43 (m,
H arom.)
3.78 (t, 2H, b-CH22); 4.11 (t, 2H, a-CH2)
6.56 – 7.45 (m,
H arom.)
5.20 (s, 2H, b-CH2); 5.87 (t, 2H, a-CH2);
6.56 – 7.45 (m, 4H, C6H4); 7.93 (d, 1H, H4,
J 7.0); 8.60 (d, 1H, H3, J 7.0); 9.58 (s, 1H, H1)
VId
VIe
VIf
2.88 d 2.82 d 3.72 s 3.81 (s, 2H, CH2); 7.21 – 7.39 (m, 5H, C6H5) 3.61 (s, 3H, CH3)
6.97 – 7.20 (m,
H arom.)
2.86 t 2.73 t 3.78 s 3.78 (s, 2H, CH3); 7.17 – 7.29 (m, 5H, C6H5) 5.21 (s, 2H, CH2); 7.31 – 7.41 (m, 5H, C6H5) 6.98 – 7.09 (m,
H arom.)
2.87 t 2.84 t 3.81 s 3.77 (s, 2H, CH2); 7.29 – 7.45 (m, 5H, C6H5)
7.07 – 7.21 (m,
H arom.)
2.96 (q, 2H, b-CH2); 3.81 (s, 2H, a-CH2)

Synthesis of 3-Alkyl- and 3,9-Dialkyl-1,2,3,4-tetrahydro-g-carbolines
517
Vol. 3, Academic Press, New York – London (1964),
g-Carboline (I). A mixture of 6.8 g (34.7 mmole) 1-phe-
nyl-1,2,3-triazolo[4, 5-c]pyridine [9] and 25.0 g paraffin was
heated for 0.5 h at 320°C, after which the temperature was
raised to 350°C and the heating was continued for 10 min.
Then the reaction mass was cooled and washed with petrole-
um ether. The residue was dissolved in a 2 N aqueous hyd-
rochloric acid solution, heated with activated charcoal, and
neutralized with a 25% aqueous ammonia solution. The pre-
cipitated light-grey crystals were separated by filtration and
dried to obtain 5.8 g (99%) of g-carboline (I); m.p.,
223 – 225°C (reported m.p., 225°C [9]).
pp. 79 – 207.
5. N. K. Kochetkov, N. F. Kucherova, L. P. Pronina, and M. I. Pet-
ruchenko, Zh. Obshch. Khim., 29(11), 3620 – 3625 (1959).
6. Yu. M. Yutilov and O. G. Éilazyan, Khim. Getrerotsikl. Soedin.,
No. 7, 992 (1981).
7. Yu. M. Yutilov and N. N. Smolyar, et al., Zh. Org. Khim., 30(3),
440 – 446 (1994).
8. M. V. Rubtsov, L. P. Yakhontov, and D. M. Krasnokutskaya, Zh.
Obshch. Khim., 29(10), 3268 – 3272 (1959).
9. O. Bremer, Liebigs Ann. Chem., 514, 279 – 298 (1934).
10. A. P. Gray, J. Am. Chem. Soc., 77(22), 5930 – 5932 (1955).
11. V. Boekelheide and C. Ainavorth, J. Am. Chem. Soc., 72(5),
2132 – 2134 (1950).
12. A. H. Cook and K. J. Reed, J. Chem. Soc., 399 – 402 (1945).
13. R. Robinson and S. Thornley, J. Chem. Soc., 125, 2169 – 2176
(1924).
14. M. V. Rubtsov and A. G. Baichikov, Synthetic Pharmaceuticals
[in Russian], Meditsina, Moscow (1971), pp. 275 – 277.
15. L. N. Yakhontov and R. G. Glushkov, Synthetic Drugs [in Rus-
sian], Meditsina, Moscow (1983), pp. 117 – 131.
REFERENCES
1. A. N. Kost, M. A. Yurovskaya, and F. A. Trofimov, Khim.
Getrerotsikl. Soedin., No. 3, 291 – 305 (1973).
2. M. D. Mashkovskii, Drugs [in Russian], Torsing, Kharkov
(1998), Vol. 1, pp. 160 – 161.
3. M. D. Mashkovskii, Drugs [in Russian], Torsing, Kharkov
(1998), Vol. 1, pp. 280 – 281.
4. R. A. Abramovitch and I. D. Spenser, in: Advances in
Heterocyclic Chemistry: The Carbolines, A. R. Katritzky (ed.),