Alternative formal synthesis of the potent D1 dopamine agonist dihydroxy-2,3,7,11b-tetrahydro-1H-naphth[1,2,3-de]isoquinoline: Dinapsoline

Full text of DOI:10.1021/jo982067z

J . Org. Chem. 1999, 64, 1407-1409
1407
with N-bromosuccinimide. The reaction proceeded regio-
selectively and in high yield at room temperature. The
benzylic hydroxyl group was protected as the methoxy-
methyl (MOM) ether using a procedure described by
Kluge et al.7 to afford 4 in excellent yield. Lithium-
bromine exchange proceeded smoothly at -78 °C. Quench-
ing with trimethyl borate followed by slow neutralization
with aqueous 1 M sodium hydrogen sulfate solution
furnished the boronic acid 5 in essentially quantitative
yield. An NMR spectrum of the crude boronic acid from
this reaction showed it to be sufficiently pure to be used
in the next step without further purification.
Alter n a tive F or m a l Syn th esis of th e P oten t
D1 Dop a m in e Agon ist
Dih yd r oxy-2,3,7,11b-tetr a h yd r o-1H-
n a p h th [1,2,3-d e]isoqu in olin e: Din a p solin e
Amjad M. Qandil,† Debasis Ghosh,‡ and
David E. Nichols*,†
Department of Medicinal Chemistry and Molecular
Pharmacology, School of Pharmacy and Pharmacal
Sciences, Purdue University, West Lafayette, Indiana 47907
Received October 14, 1998
Using typical conditions for the Suzuki cross-coupling
reaction, a mixture of 4-bromoisoquinoline, the aryl-
boronic acid, degassed aqueous sodium carbonate, and a
catalytic amount of tetrakis(triphenylphosphine)palladium-
(0) was heated to reflux in degassed 1,2-dimethoxy-
ethane.8 After extraction and evaporation of the solvents,
the crude residue was treated with trifluoroacetic acid
in dichloromethane to afford the desired product 6 in very
good yield as an off-white solid. Reduction using sodium
cyanoborohydride in methanolic-HCl gave the 1,2,3,4-
tetrahydroisoquinoline 7 in quantitative yield, as shown
in Scheme 3. The amine 7 was then treated with
p-toluenesulfonyl chloride in the presence of N,N-diiso-
propylethylamine to afford N-p-toluenesulfonylamide 2
in excellent yield.
In tr od u ction
We have previously reported the synthesis and phar-
macological evaluation of 8,9-dihydroxy-2,3,7,11b-tet-
rahydro-1H-naphth[1,2,3-de]isoquinoline, dinapsoline (1),1
a potent full dopamine D1 agonist containing a rigid
â-phenyldopamine pharmacophore, with potential anti-
parkinsonian activity. The original synthesis was rather
long and unsuitable for production of large quantities.
This note describes the highly efficient preparation of key
intermediate 2 in the original synthetic pathway for
dinapsoline comprising therefore an alternative formal
synthesis of dinapsoline.
Con clu sion s
This synthesis proved to be highly efficient to prepare
large quantities of intermediate 2. This intermediate will
be used to obtain dinapsoline and other dinapsoline
analogues.
Resu lts a n d Discu ssion
Exp er im en ta l Section
The new retrosynthetic route is illustrated in Scheme
1. In 1994 Miller and Svoboda2 described the synthesis
of a 4-phenyl-1,2,3,4-tetrahydroisoquinoline from 4-bro-
moisoquinoline based on the Miyaura-Suzuki cross-
coupling reaction (more commonly known as the Suzuki
cross-coupling reaction) for the preparation of diaryl
compounds.3,4 Their report provided the elements for an
improved synthesis of dinapsoline, with the challenge
being in our case to prepare the necessary boronic acid.
This synthesis is illustrated in Scheme 2.
Gen er a l Com m en ts. Melting points are uncorrected. High-
resolution CI and EI mass spectra were obtained within 0.0015
m/z, unless otherwise noted. The ionization gas for CIMS and
high-resolution CIMS was isobutane.
6-Br om o-2,3-d im eth oxyben zyl Alcoh ol (3). To a solution
of 45 g (0.268 mol) of 2,3-dimethoxybenzyl alcohol in 200 mL of
THF was added 47.6 g (0.268 mol) of N-bromosuccinimide (NBS).
The suspension was stirred until all the NBS had dissolved. The
THF was then evaporated, and the residue was taken up in 500
mL of diethyl ether. The insoluble succinimide was removed by
filtration, and the ethereal layer was washed twice with 2 N
aqueous NaOH. The organic layer was dried (MgSO4) and
filtered, and the solvent was evaporated. The residue was
crystallized from ethyl acetate-hexane to yield 61.47 g (93%)
The benzyl alcohol 3 was previously prepared through
a five-step synthesis.5,6 As illustrated in Scheme 2, we
were able to obtain the same intermediate by brominat-
ing commercially available 2,3-dimethoxybenzyl alcohol
1
as a white solid: mp 76 °C (lit. 74-75 °C). H NMR: δ 2.32 (t,
1H, -OH, J ) 7 Hz); δ 3.84 (s, 3H, O-CH3); δ 3.89 (s, 3H,
O-CH3); δ 4.81 (d, 2H, Ar-CH2-O, J ) 7 Hz); δ 6.76 (d, 1H,
Ar-H, J ) 9 Hz); δ 7.25 (d, 1H, Ar-H, J ) 9 Hz). CIMS m/z:
(M, M + 2) 246 and 248, ((M + H) - 18) 229, ((M + H + 2) -
18) 231.
* Corresponding author. Phone: (765) 494-1461. Fax: (765) 494-
1414. E-mail: drdave@pharmacy.purdue.edu.
† Purdue University.
‡ Present address: AVI BioPharma Inc., 4575 Research Way, Suite
200 Corvallis, OR 97333.
6-B r o m o -2,3-d im e t h o x y (m e t h o x y m e t h o x y )m e t h y l-
ben zen e (4). Sodium hydride (8.55 g; 60% suspension in mineral
oil; 0.213 mol) was rinsed with hexane several times and then
suspended in 250 mL of dry THF, and the mixture was placed
under argon and cooled in an ice bath. A solution of 44 g (0.178
mol) of 3 in 250 mL of dry THF was added, and the mixture
(1) Ghosh, D.; Snyder, S. E.; Watts, V. J .; Mailman, R. B.; Nichols,
D. E. J . Med. Chem. 1996, 39, 549-555.
(2) Miller, R. B.; Svoboda, J . Synth. Commun. 1994, 24, 1187-1193.
(3) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(4) Stavenuiter, J .; Hamzink, M.; Hulst, R.; Zomer, G.; Westra, G.;
Kriek, E. Heterocycles 1987, 26, 2711-2716.
(5) Kametani, T.; Honda, T.; Inoue, H.; Fukumoto, K. J . Chem. Soc.,
Perkin Trans. 1 1976, 1221-1225.
(6) Kunitomo, J .-I.; Miyata, Y.; Oshikata, M. Chem. Pharm. Bull.
1985, 33, 5245-5249.
(7) Kluge, A. F.; Untch, K. G.; Fried, J . H. J . Am. Chem. Soc. 1972,
94, 7827-7832.
(8) Wustrow, D. J .; Wise, L. D. Synthesis 1991, 993-995.
10.1021/jo982067z CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/30/1999

1408 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 1
Sch em e 2
Sch em e 3
was heated at reflux for 1 h. The reaction was left to cool to
room temperature, and then 13.5 mL (14.33 g, 0.178 mol) of
methoxymethyl chloride was added and the solution was stirred
at reflux for another 1 h. After cooling to room temperature the
mixture was added slowly to 500 mL of ice-water, and the THF
was then evaporated. The aqueous layer was extracted with
diethyl ether. The combined organic layers were washed with
water, dried (MgSO4), filtered, and then concentrated. The oily
residue was distilled (95 °C, 60 mmHg) to afford 48.0 g of a
colorless oil (92.6%). NMR: δ 3.44 (s, 3H, O-CH3); δ 3.83 (s,
3H, O-CH3); δ 3.855 (s, 3H, O-CH3); δ 4.719 (s, 2H, Ar-CH2-
O); δ 4.744 (s, 2H, O-CH2-O); δ 6.767 (d, 1H, Ar-H, J ) 8.5
Hz); δ 7.27 (d, 1H, Ar-H, J ) 8.5 Hz). CIMS m/z: 290, 292 (M+,
52; M + 2, 50); 229, 231 (M+ - 61, 98; M+ + 2 - 61, 100). Anal.
Calcd for C11H15BrO4: C, 45.38; H, 5.19. Found: C, 45.54; H,
5.19.
3,4-Dim eth oxy-2-(m eth oxym eth oxy)m eth ylbor on ic Acid
(5). The methoxymethyl ether 4 (48 g; 0.165 mol) was dissolved
in 300 mL of dry diethyl ether and stirred under argon at -78
°C. A solution of n-butyllithium (123.8 mL of 1.6 M) was cooled
to -78 °C, then cannulated into the solution of 4, and the
mixture was left to stir for 15 min. Trimethyl borate 56.2 mL
(51.43 g, 0.495 mol) was added rapidly to the cold reaction. The
mixture was left to stir and allowed to warm to room temper-
ature over 4 h. The reaction was neutralized by dropwise
addition of 200 mL of 1 M aqueous NaHSO4. The ethereal layer
was dried (MgSO4), filtered, and concentrated. An oily residue
was obtained in essentially quantitative yield (42.2 g) that was
used for the subsequent reaction without further purification.
A sample for NMR was recrystallized from diethyl ether-
hexane, but drying the crystals under high vacuum led to
apparent desolvation with the formation of a white gum. 1H
NMR (500 MHz, CDCl3): δ 3.39 (s, 3H, OCH3); δ 3.81 (s, 3H,
O-CH3); δ 3.87 (s, 3H, O-CH3); δ 4.7 (s, 2H, Ar-CH2-O); δ
4.8 (s, 2H, O-CH2-O); δ 6.5 (s, 2H, (B-(OH)2); δ 6.9 (d, 1H,
Ar-H, J ) 8.5 Hz); δ 7.6 (d, 1H, Ar-H, J ) 8.0 Hz).
4-(3,4-Dim e t h oxy-2-h yd r oxym e t h ylp h e n yl)isoq u in o-
lin e (6). To 25 g (0.120 mol) of 4-bromoisoquinoline (Aldrich) in
200 mL of dimethoxyethane (DME) under an atmosphere of
argon were added all the crude product, 5 (0.165 mol), from the
previous reaction and 165 mL of aqueous 2 M sodium carbonate
solution. To this mixture was added 5 g (3.6 mol %) of tetrakis-
(triphenylphosphine)palladium(0), and the reaction was heated
at reflux for 10 h. The biphasic mixture was allowed to cool, and
the layers were separated. The aqueous layer was extracted with
diethyl ether, and the combined organic layers were washed with
cold 2 N sodium hydroxide solution, then water, and finally dried
(Na2SO4). The solvent was filtered and evaporated, the residue
was taken up into trifluoroacetic acid (TFA) solution in dichlo-
romethane (20 mL of TFA in 100 mL of CH2Cl2), and the solution
was stirred overnight. The reaction was then diluted with 300
mL of water, carefully basified with 2 N sodium hydroxide
solution, and then extracted with dichloromethane. The organic
extracts were dried (Na2SO4) and filtered, and the solvent was

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1409
evaporated. The residue was crystallized from diethyl ether to
afford 30.4 g (84%) of an off-white powder: mp 128-130 °C. H
6H, O-CH3); δ 3.87 (d, 1H, Ar-CH2-N, J ) 16.0 Hz); δ 3.99 (d,
1H, Ar-CH2-N, J ) 16.0 Hz); δ 4.32 (t, 1H, Ar-CH-CH2N, J
) 6.5 Hz); δ 4.64 (m, 3H, Ar-CH2-OH and -NH); δ 6.55 (d,
1H, Ar-H, J ) 8.5 Hz); δ 6.76 (d, 1H, Ar-H, J ) 8.0 Hz); δ 6.9
(d, 1H, Ar-H, J ) 8.5 Hz); δ 6.99 (t, 1H, Ar-H, J ) 7.5 Hz); δ
7.05 (m, 2H, Ar-H). CIMS m/z: 300 (M+ + 1, 45); 282 (M+ + 1
- 18, 100). Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N,
4.68. Found: C, 72.00; H, 7.04; N, 4.60.
1
NMR: δ 3.96 (s, 3H, O-CH3); δ 4.02 (s, 3H, O-CH3); δ 4.34 (d,
1H, Ar-CH2-O, J ) 12.5 Hz); δ 4.4 (d, 1H, Ar-CH2-O, J )
12.0 Hz); δ 7.01 (s, 2H, Ar-H); δ 7.56 (d, 1H, Ar-H, J ) 8.5
Hz); δ 7.63 (m, 2H, Ar-H); δ 7.79 (d, 1H, Ar-H, J ) 8.5 Hz); δ
8.40 (s, 1H, Ar-H); δ 9.23 (s, 1H, Ar-H). CIMS m/z: 296 (M+
+
H, 100); 278 (M+ + H - 18, 76). Anal. Calcd for C18H17NO3: C,
73.20; H, 5.80; N, 4.74. Found: C, 73.02; H, 5.82; N, 4.70.
4-(3,4-Dim et h oxy-2-h yd r oxym et h ylp h en yl)-1,2,3,4-t et -
r a h yd r oisoqu in olin e (7). The isoquinoline 6 (30 g; 101.6 mmol)
was dissolved in 250 mL of anhydrous methanol under an
atmosphere of argon. To that solution was added 38.4 g (0.611
mol) of powdered sodium cyanoborohydride in portions. A few
drops of methanolic bromocresol green solution were added,
which turned the color of the reaction blue. The reaction was
acidified (the color of the reaction turned yellow) and maintained
acidic by adding 10% methanolic-HCl solution though a dropping
funnel. When the yellow color persisted, the solution was basified
with 2 N NaOH solution, and the methanol was evaporated. The
residue was partitioned between 200 mL of water and 200 mL
of dichloromethane, and the aqueous layer was reextracted with
dichloromethane. The organic layers were dried (Na2SO4), and
the solvent was filtered and evaporated. The residue was
triturated with diethyl ether to afford 29.04 g (95.5%) of the
amino alcohol 7 as a white solid: mp 160-162 °C. 1H NMR (500
MHz NMR, DMSO): δ 2.8 (dd, 1H, ArCH-CH2-N, J ) 7.5, 12.5
Hz); δ 3.19 (dd, 1H, ArCH-CH2-N, J ) 5.5, 13.0 Hz); δ 3.74 (s,
4-(3,4-Dim eth oxy-2-h yd r oxym eth ylp h en yl)(N-p-tolu en e-
su lfon yl)-1,2,3,4-tetr a h yd r oisoqu in olin e (2). The amino al-
cohol 7 (20 g; 66.8 mmol) was dissolved in 250 mL of dichlo-
romethane under an atmosphere of argon. To that solution 12.74
g (66.79 mmol) of p-toluenesulfonyl chloride was added, followed
by 15.13 mL (11.23 g; 86.85 mmol) of N,N-diisopropylethylamine,
which was added slowly via syringe. The solution was stirred
at room temperature for 13 h. The dichloromethane solution was
washed with 2 N HCl and then dried (MgSO4). After filtration,
the solvent was evaporated, and the residue was crystallized
from ethyl acetate to afford 25.95 g (85.8%) of the N-p-tosyl
amido alcohol as a white solid: mp 158-160 °C (lit. 166-168
°C). 1H NMR and chemical ionization MS were identical to
material prepared by the method of Ghosh et al.1
Ack n ow led gm en t. This work was supported by
NIH Grant MH42705.
J O982067Z