Organic Process Research & Development 2007, 11, 463−465
Improved and Practical Synthesis of 6-Methoxy-1,2,3,4-
tetrahydroisoquinoline Hydrochloride
H. Marlon Zhong,* Frank J. Villani, and Ramzy Marzouq
Chemical DeVelopment, Johnson and Johnson Chemical and Pharmaceutical DeVelopment,
Spring House,PennsylVania 19477, U.S.A.
Abstract:
-Methoxy-1,2,3,4-tetrahydroisoquinoline (1) or its hydrochlo-
ride salt (4) is an expensive chemical with limited commercial
availability. We report an improved and practical synthesis of
practical synthesis of tetrahydroisoquinoline analogues, the
6
methodology was not applied to the synthesis of our targeted
molecule. In addition to the direct condensation of 2-(3′-
methoxyphenyl)ethylamine with formaldehyde, other litera-
ture approaches required protection of the amine functionality
prior to the acid-catalyzed condensation and a deprotection
4
from inexpensive 2-(3-methoxyphenyl)ethylamine (2) using a
Pictet-Spengler condensation via a novel aminal intermediate.
The synthesis significantly lowers the cost and provides easy
access to 6-methoxy-1,2,3,4-tetrahydroisoquinoline or its HCl
salt on a large scale.
2
a,5
step after the condensation.
An alternative approach,
6
reported by Sall and Grunewald, used a Friedel-Crafts type
cyclization of methyl 2-(3′-methoxyphenyl)ethyl carbamate
with polyphosphoric acid (PPA) to give a mixture of
6
-methoxy- and 8-methoxy-3,4-dihydroisoquinolinones in a
ratio of 2:1, respectively. Separation of the regioisomers by
chromatography and subsequent reduction with lithium
aluminum hydride yielded 6-methoxy- and 8-methoxy-
Introduction
During the course of one of our recent projects we
required substantial amounts of 6-methoxy-1,2,3,4-tetrahy-
droisoquinoline (1) as a starting material. While it is
commercially available, it is very expensive (>$400/g) and
available only in milligram quantities as listed by a few
chemical sources. Although several syntheses of this com-
pound have been reported in the literature, none is convenient
to carry out on a large scale. Among those approaches, the
most direct method for synthesis of this tetrahydroisoquino-
line is a Pictet-Spengler type condensation of 2-(3′-
1,2,3,4-tetrahydroisoquinolines. Although the procedure was
recently utilized by Mewshaw and co-workers for their
7
medicinal chemistry research, the poor regioselectivity of
cyclization and the harsh reaction conditions prevented its
application in large-scale synthesis.
Results and Discussion
To fulfill our need of a large quantity of 6-methoxy-
1,2,3,4-tetrahydroisoquinoline (1), we evaluated the Pictet-
Spengler condensation methodology starting from the com-
mercially available 2-(3′-methoxyphenyl)ethylamine (2). The
reaction of 2 with aqueous formaldehyde (37%) in 1 N
aqueous HCl solution was found to be very slow at room
temperature, resulting only in 50% conversion after 4 days.
However, we discovered the reaction could be completed in
just 1 h at 60 °C. After basification of the reaction mixture
to pH ∼12 using 3 N aqueous NaOH solution, an off-white
solid product was precipitated and isolated. Comparing this
solid to an authentic sample of 1 (an oil) showed that the
isolated solid product had the same HPLC retention time
and LC/MS spectrum as that of the authentic sample. The
1
methoxyphenyl)ethylamine (2) with formaldehyde. Several
research groups have used this approach to obtain the target
compound in small quantities. The product resulting from
the direct condensation of 2-(3′-methoxyphenyl)ethylamine
with formaldehyde is an oil making the isolation and
2
purification process difficult for large-scale synthesis. Bucks
has reported a procedure for the direct isolation of the HCl
salt of 6-methoxy-1,2,3,4-tetrahydroisoquinoline (4), but the
procedure requires a time-consuming evaporation of aqueous
HCl solution to dryness. Ruchirawat and co-workers re-
ported a direct synthesis of tetrahydroisoquinoline analogues
3
4
using paraformaldehyde and formic acid. Their workup
involved a process-unfavorable step, distillation of formic
acid to dryness, followed by isolation of the products as their
oxalate salts. Although this approach represented the most
1
H NMR spectrum of the isolated solid product was similar
but not identical showing only one set of peaks evidently
from a single compound. However it contained two more
nonexchangeable protons as compared to the authentic
*
To whom correspondence should be addressed. E-mail: hzhong@
prdus.jnj.com.
1
sample of 1, which were found to be a CH
2
unit by H NMR
(1) (a) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 151. (b) Ivanov,
I.; Venkov, A. Heterocycles 2001, 55, 1569. (c) Bates, H. A. J. Org. Chem.
1
3
and C NMR analyses. Apparently the isolated solid was
not the desired product 1. Based on the data, we concluded
that the isolated solid was bis(6-methoxy-3,4-dihydroiso-
1
983, 48, 1932-1934. (d) Bates, H. A.; Bagheri, K.; Vertino, P. M. J. Org.
Chem. 1986, 51, 3061-3063.
(
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(
3) Buck, J. S. J. Am. Chem. Soc. 1934, 56, 1769-1771.
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(
1
0.1021/op7000468 CCC: $37.00 © 2007 American Chemical Society
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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Published on Web 04/25/2007