Arch. Pharm. Chem. Life Sci. 2012, 345, 81–85
Efficient Synthesis of Aripiprazole, Buspirone and NAN-190
83
alkylation of amines procedure is an attractive synthetic
alternative for large-scale production of the title drugs.
In these syntheses the products were prepared from
commercially available reagents and were isolated in very
good yields and purity.
aldehyde dimethyl acetal in 15 mL of DMSO, 8.28 g
(0.060 mol) of potassium carbonate and 1.61 g (5 mmol) of
TBAB were added. The mixture was stirred and heated at
115 ꢀ 58C for 4 h. Next, the solvent and volatile materials
were distilled off under reduced pressure and 50 mL of
water was added to the residue. The product was extracted
two times with toluene (50 mL and 25 mL). The extract
was washed with 10% aqueous solution of sodium hydroxide
and toluene was evaporated under reduced pressure.
The oil residue was heated up to about 558C and 15 mL
of ethanol was added. Then the solution was cooled
down to room temperature. Light beige precipitate
formed, which was filtered off, washed with cold ethanol
and dried; 13.40 g (96% yield) of raw 7-(4,4-dimethoxybutoxy)-
3,4-dihydro-1H-quinolin-2-one 7a was obtained, which
was 95% pure (by UPLC). After crystallization from
ethanol 7a had m.p. 85–878C and 98% (UPLC) purity.
1H-NMR (500 MHz, CDCl3): 1.76–1.85 (m, 4H, 2 CH2), 2.62
(t, 2H, J ¼ 7.3 Hz, CH2), 2.89 (t, 2H, J ¼ 7.4 Hz, CH2), 3.34
(s, 6H, 2 CH3), 3.95, (t, 2H, J ¼ 6.2 Hz, CH2), 4.43, (t,
1H, J ¼ 5.5 Hz, CH), 6.38 (d, 1H, J ¼ 2.4 Hz, CHAryl), 6.51
(d,d, 1H, J ¼ 8.3 Hz, J ¼ 2.4 Hz, CHAryl), 7.03 (d, 1H,
J ¼ 8.3 Hz, CHAryl), 8.94 (s, 1H, NH). 13C-NMR (125 MHz,
CDCl3): 24.39, 24.52, 29.04, 31.02, 52.77 (2C), 67.64, 102.24,
104.21, 108.70, 115.64, 128.51, 138.19, 158.58, 172.22.
MS-ESIþ: m/z 280 [MþH]þ. Anal. calcd. for C15H21NO4
(279.33): C, 64.50; H, 7.58; N, 5.01. Found: C, 64.71; H, 7.39;
N, 5.30.
Generally, the experimental results indicate that the
described procedure of reductive alkylation of amines allows
introduction of an alkyl spacer to a molecule under mild
reaction conditions, whilst usually 1,v-dihalogenalkanes
have been applied for construction of the spacers.
Experimental section
General
Melting points were determined on a Bo¨etius apparatus and
are uncorrected. 1H-NMR and 13C-NMR spectra were recorded
on a Varian spectrometer, using deuterated chloroform or
deuterated dimethylsulfoxide as the solvents. The chemical
shifts are expressed as d values in ppm against TMS as an
internal standard. Purities and molecular masses of com-
pounds were determined by Waters Acquity UPLC, coupled
to Waters Acquity SQD mass spectrometer. Elemental
analyses (C, H, N) were performed on a Perkin-Elmer 2400
analyzer, and the results are within ꢀ0.4% of the calculated
values. The reactions were monitored by TLC on silica-gel
plates (Merck 60F254) using chloroform/methanol (9:1) as
eluent. Starting materials, solvents, and reagents were pur-
chased from commercial sources and were used without
further purification.
8-(4,4-Dimethoxybutyl)-8-azaspiro[4.5]dekane-7,9-dione
7b
UPLC/MS analysis
Samples were dissolved in methanol. The UPLC/MS system
consisted of a Waters Acquity UPLC, coupled to Waters
Acquity SQD mass spectrometer (electrospray ionization
mode, single quadrupole). All analyses were carried out using
an Acquity BEH C18, 2.1 ꢁ 50 mm, 1.7-mm column. Eluent
flow rate of 350 mL/min and a gradient of 5–95% of B over
1.8-min period, followed by holding for 1 min at 95% meth-
anol were used. Eluent A: 0.02% HCOOH in water; eluent
B: methanol. Nitrogen was used for both: desolvation and
cone gas with flow rates of 800 L/h and 50 L/h, respectively.
Source temperature was 1208C and the desolvation tempera-
ture was 3508C. The data were obtained in scan mode ranging
from 100 to 1100 m/z with a scan rate of 9000 Da/s (alternat-
ing both ESIþ and ESIꢂ modes of ESI), giving 4.5 points of TIC
per second.
Oil, yield 96%, purity (UPLC) 95%. 1H-NMR (500 MHz, CDCl3):
1.48–1.52 (m, 4H, 2 CH2), 1.56–1.59 (m, 4H, 2 CH2), 1.70–1.73
(m, 4H, 2 CH2), 2.58 (s, 4H, 2 CH2), 3.31 (s, 6H, 2 CH3),
3.77, (t, 2H, J ¼ 7.1 Hz, CH2), 4.37, (t, 1H, J ¼ 5.3 Hz, CH).
13C-NMR (125 MHz, CDCl3): 23.04, 24.08 (2C), 29.82,
37.44 (2C), 39.34, 44.73 (2C), 52.68 (2C), 104.06, 172.02 (2C).
MS-ESIþ: m/z 284 [MþH]þ. Anal. calcd. for C15H25NO4 (283.36):
C, 63.58; H, 8.89; N, 4.94. Found: C, 63.77; H, 8.62;
N, 4.84.
2-(4,4-Dimethoxybutyl)isoindoline-1,3-dione 7c
Oil, yield 95%, purity (UPLC) 94%. 1H-NMR (500 MHz, CDCl3):
1.63–1.67 (m, 2H, CH2), 1.73–1.79 (m, 2H, CH2), 3.31 (s, 6H,
2 CH3), 3.71, (t, 2H, J ¼ 7.1 Hz, CH2), 4.39, (t, 1H, J ¼ 5.7 Hz,
CH), 7.76 (d, d, 2H, J ¼ 5.5 Hz, J ¼ 3.1 Hz,
2 CHAryl),
7.84 (d, d, 2H, J ¼ 5.4 Hz, J ¼ 3.0 Hz, 2 CHAryl). 13C-NMR
(125 MHz, CDCl3): 23.78, 29.83, 37.62, 52.86 (2C),
104.02, 123.13 (2C), 132.07, 133.84 (3C), 168.32 (2C).
MS-ESIþ: m/z 264 [MþH]þ. Anal. calcd. for C14H17NO4
(263.29): C, 63.87; H, 6.51; N, 5.32. Found: C, 63.68; H, 6.55;
N, 5.09.
Procedure for the synthesis of the acetals 7a–c, illustrated
by the preparation of 7-(4,4-dimethoxybutoxy)-3,4-dihydro-
1H-quinolin-2-one 7a
To a solution of 8.16 g (0.050 mol) of 7-hydroxy-3,4-dihydro-
1H-quinolin-2-one 4a and 9.15 g (0.060 mol) of 4-chlorobutyr-
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