A short and efficient asymmetric synthesis of (1S,2R)-(+)-5-methoxy-1- methyl-2-(di-n-propylamino)tetralin hydrochloride (UH-232)

Article abstract of DOI:10.1016/S0957-4166(99)00333-X

A general practical asymmetric synthesis of (1S,2R)-(+)-5-methoxy-1- methyl-2-(di-n-propylamino)tetralin hydrochloride (UH-232) was developed in a short and efficient method in high optical purity starting from commercially available 5-methoxy-1-tetralone. Asymmetric hydroboration of 5-methoxy-1- methyl-3,4-dihydronaphthalene with monoisopinocampheylborane followed by treatment with NaOH/H₂O₂ afforded key intermediate tetrahydronaphthol 4. Compound 4 was converted to the target molecule 1 using straightforward reactions.

Full text of DOI:10.1016/S0957-4166(99)00333-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3281–3283
A short and efficient asymmetric synthesis of (1S,2R)-(+)-
5-methoxy-1-methyl-2-(di-n-propylamino)tetralin hydrochloride
(UH-232)
N. Laxma Reddy,∗ Iris Francesconi and Emile M. Bellott
Pharm-Eco Laboratories, Inc., 128 Spring Street, Lexington, MA 02421, USA
Received 30 July 1999; accepted 1 August 1999
Abstract
A general practical asymmetric synthesis of (1S,2R)-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin
hydrochloride (UH-232) was developed in a short and efficient method in high optical purity starting
from commercially available 5-methoxy-1-tetralone. Asymmetric hydroboration of 5-methoxy-1-methyl-3,4-
dihydronaphthalene with monoisopinocampheylborane followed by treatment with NaOH/H2O2 afforded key
intermediate tetrahydronaphthol 4. Compound 4 was converted to the target molecule 1 using straightforward
reactions. © 1999 Elsevier Science Ltd. All rights reserved.
It has been reported earlier that (1S,2R)-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin hy-
drochloride (1, UH-232) is a dopamine (DA) antagonist with preferential action on presynaptic DA
autoreceptors, while the corresponding (1R,2S)-(−) enantiomer, particularly the hydroxy analog, appears
to be a centrally acting DA receptor agonist.1 The selectivity of compound 1 for DA autoreceptors makes
it interesting as a pharmacological tool and also potentially as a therapeutic agent.2 The compounds fit
a stereomodel of dopaminergic agonists and antagonists in which the preferred direction of the lone pair
of the nitrogen atom or hydrogen of the ammonium ion determines an agonist or antagonist profile.3
Because of the opposite profiles of the enantiomers, it is necessary to synthesize 1 with high optical
purity.
∗
Corresponding author. E-mail: lreddy@pharmeco.com
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00333-X

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N. L. Reddy et al. / Tetrahedron: Asymmetry 10 (1999) 3281–3283
The limited synthetic methods in the literature for 1 require multiple steps and chemical resolution for
separation of the enantiomers. Furthermore, the methods use commercially inaccessible and/or difficult to
prepare starting materials such as 5-methoxy-2-tetralone. For example, the initial synthesis of 1 involved
a mixture of diastereomers which could not be separated by fractional crystallizations and/or column
chromatography.1 After repeated fractional crystallizations of the corresponding trifluoroacetamide
derivatives, it was possible to isolate the compound in 96% diastereomeric excess as determined by
GC analysis.
Here, we report a short and efficient asymmetric synthesis of 1 (UH-232) in 88% enantiomeric purity
as determined by chiral HPLC. More importantly the synthesis starts from a commercially available
5-methoxy-1-tetralone (2). Tetralone 2 was alkylated with MeMgBr in t-butyl methyl ether (t-BME)
followed by treatment with p-TSA in toluene to afford 1-methyl-3,4-dihydronaphthalene (3) in 79%
yield.4 Hydroboration of 3 with monoisopinocampheylborane (generated from commercially available
R-Alpine-Boramine™ with BF3–Et2O or prepared from α-pinene as per literature method5) in THF at
−16 to −20°C followed by treatment with NaOH and 30% H2O2 resulted in trans-5-methoxy-1-methyl-
1,2,3,4-tetrahydro-2-naphthol (4) in 71% yield after column chromatography.6 The tosylate prepared
(tosyl chloride/pyridine) in 86% yield was treated with sodium azide (Caution!) in H2O–DMF to give
cis-1-methyl-2-azido-5-methoxy-1,2,3,4-tetrahydronaphthaline (5) in 84% yield (Scheme 1).
Scheme 1. Reagents: (a) MeMgBr/t-BME; (b) p-TSA/toluene; (c) IPC-BH2/THF; (d) NaOH/H2O2; (e) TsCl/Pyr; (f)
NaN3/H2O–DMF; (g) LAH/THF; (h) CH3CH2COCl/Et3N; (i) 1.0 M HCl/MeOH
Reduction of the azide (5) with LAH in THF afforded the amine 6 in 82% yield. Reductive alkylation of
6 with propionyl chloride followed by LAH in THF afforded cis-1-methyl-2-(n-propylamino)-5-methoxy
tetralin (7) in 74% yield. Chiral HPLC/MS analysis of the amine indicated an enantiomeric ratio of 94:6.
The specific rotation of 7·HCl ([α]=(+)−48.8 (c 1.0, EtOH) was found to be in comparable range with
related analogs.1
Compound 7, upon treatment with propionyl chloride, followed by reduction of the amide with LAH in
THF, afforded the desired product in 81% yield. The ratio of enantiomers was determined by chiral HPLC
analysis (Chiral column ULTRON ES-OVM, Detector UV @ 220 nm, NH4OAc buffer–CH3CN 90:10 as
mobile phase) and were found to be 94:6 (area%) with retention times of 5.72 and 4.34 min, respectively,
and isomers were confirmed by MS. The free base was converted to its HCl salt (1, UH-232)7 with 1.0
M HCl–MeOH.
In summary, we have developed a short and efficient asymmetric synthesis of 5-methoxy-1-methyl-2-
(di-n-propylamino)tetralin hydrochloride (1, UH-232) in high optical purity starting from commercially

N. L. Reddy et al. / Tetrahedron: Asymmetry 10 (1999) 3281–3283
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available and inexpensive 5-methoxy-1-tetralone. This synthesis enabled us to generate (+)-UH-232 in
multigram quantities for further pharmacological studies.
Acknowledgements
We thank Drs. Mark Froimowitz and Luning Han for helpful discussions and Dr. Carrie Liu for
analytical service. This work was supported in whole or in part with Federal funds from the National
Institute of Drug Abuse (NIDA), National Institute of Health, under Contract No. NO1DA-7-8082.
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