4
06
J . Org. Chem. 1998, 63, 406-407
Alter n a tive Syn th esis of Sep tic Sh ock
Sch em e 1
Ca n d id a te
,4-Dih yd r o-3,3-d im eth ylisoqu in olin e
N-Oxid e (MDL 101002) Utilizin g a n
3
Im p r oved P ictet-Sp en gler Rea ction
Sch em e 2a
Timothy J . N. Watson
Chemical Development, Hoechst Marion Roussel
Research Institute, 2110 East Galbraith Road,
Cincinnati, Ohio 45215-6300
Received September 29, 1997
A series of compounds incorporating a dihydroiso-
quinoline-based nitrone has drawn particular interest for
the treatment of stroke and septic shock.1 One in
particular, 3,4-dihydro-3,3-dimethylisoquinoline N-oxide
(MDL 101002, 6), has previously been synthesized utiliz-
ing a modified Bischler-Napieralski reaction. The key
reaction to form the quinoline ring system via this route
is shown in Scheme 1.1b This reaction proved to be very
tedious and gave poor results on a larger scale. It became
clear that alternative chemistry needed to be investigated
if larger quantities of material were to be obtained.
A more direct route could be envisioned utilizing a
Pictet-Spengler reaction on phentermine hydrochloride
a
(
a) p-TsCl, NEt3, CH2Cl2 (99%); (b) BF3.OEt2, DMM (99%); (c)
KOH, MeOH, reflux (90%); (d) Na, naphthalene, DMF (86%); (e)
H2O2, Na2WO4.
1a,b
failed to produce a tetrahydroisoquinoline in reasonable
amounts.2
Treating 2 in dimethoxymethane (DMM) with boron
trifluoride diethyl etherate produced 1,2,3,4-tetrahydro-
,3-dimethyl-2-[(4-methylphenyl)sulfonyl]isoquinoline (3)
(1). Although there has been limited success, the dif-
3
ficulty with which unsubstituted aromatic pheneth-
ylamines undergo the Pictet-Spengler reaction is well-
recognized.2
in an isolated yield of 99%. The DMM serves as the
solvent as well as the formaldehyde source, while the
boron trifluoride diethyl etherate facilitates formaldehyde
formation and Pictet-Spengler cyclization. It is quite
unusual for the solvent and catalyst both to serve two
unique and essential functions resulting in such an
efficient reaction. It should also be noted that the
reaction does not proceed in the absence of the tosylate
functionality.2
In 1977, Ito and Tanaka reported the ease at which
N-sulfonylphenethylamines underwent cyclization in the
presence of 37% formaldehyde and boron trifluoride
diethyl etherate.3 We report herein an alternative
synthesis of MDL 101002 (6) via a modified Pictet-
Spengler reaction following the Ito-Tanaka protocol, a
highly efficient procedure having the potential of readily
producing kilogram quantities of MDL 101002.
,3
Removal of the tosylate can be accomplished in two
fashions: Refluxing potassium hydroxide in methanol
will afford the elimination product 3,4-dihydro-3,3-di-
Resu lts
methylisoquinoline (4) in 90% yield.4 Alternatively,
treatment of 3 with sodium naphthalenide5 gives the
Scheme 2 summarizes the synthesis of MDL 101002
6). Commercially available phentermine hydrochloride
1) was transformed into N-(1,1-dimethyl-2-phenylethyl)-
-methylbenzenesulfonamide (2) using standard tosyla-
tion conditions. Any attempt to directly cyclize 1 under
original Pictet-Spengler conditions (HCl, “methylal”)
1
,2,3,4-tetrahydro-3,3-dimethylisoquinoline (5) in 86%
(
(
4
yield containing 14% of the elimination product 4 as
well. Reacting compound 4 or 5 with sodium tungstate
will afford the desired MDL 101002 as previously
reported.1
3
a,b
2
Although there are other limited examples of unsub-
stituted aromatic phenethylamines undergoing the Pic-
tet-Spengler reaction in modest yields, we feel this
modified Itom-Tanaka reaction may have some minor
advantages. The ability to mildly generate formaldehyde
in an anhydrous environment, thus limiting human
exposure, is always advantageous. The extreme efficiency
of this example has potential for rapid access into larger
quantities of MDL 101002 as well as analogues of
dihydroisoquinoline-based nitrones from nonactivated
phenethylamines.
(
1) (a) Bernotas, R. C.; Hay, D. A.; Carr, A. A.; Nieduzak, T. R.;
Adams, G.; French, J . F.; Ohlweiler, D. F.; Thomas, C. E. Bioorg. Med.
Chem. Lett 1996, 6 1105-1110. (b) Adams, G.; Carr, A.; Bernotas, R.
Tetrahedron 1996, 52 (19), 6519-6526. (c) Larsen, R. D.; Reamer, R.
A.; Corley, E. G.; Davis, P.; Grabowski, E. J . J .; Reider, P. J .; Shinkai,
I., J . Org. Chem. 1991, 56, 6034-6036. (d) Thomas, C. E.; Carney, J .
M.; Bernotas, R. C.; Hay, D. A.; Carr, A. A. Neurobiol. No Oh 1994,
7
38, 243-249. (e) French, J . F.; Thomas, C. E.; Downs, T. R.; Ohlweiler,
D. F.; Carr, A. A.; Dage, R. C. Circul. Shock 1994, 43, 130-136.
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(
A. C.; Snyder, H. R. In Organic Reactions; Whaley, W. M., Govinda-
chari, T. R., Eds.; J . Wiley and Sons, Inc.:T New York, 1951; Vol. 6,
1
51. (b) Cook, J . M.; Cox, E. D. Chem. Rev. 1995, 95, 1797-1842. (c)
Goel, O. P.; Chen, H. G. Synth. Commun. 1995, 25 (1), 49-56. (d) Kubo,
A., Yamada, E.; Kawakami, N.; Saito, N. Chem. Pharm. Bull. 1989,
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7, (6), 1493-1499. (e) Heterocyclic Compounds; J . Wiley and Sons,
(4) Remers, W. A.; Roth, R. H.; Gibs, G. J .; Weiss, M. J . J . Org.
Chem. 1971, 36, 1232-1240.
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Published on Web 01/23/1998