A facile, one-pot procedure for the preparation of 2-phenyl-1,3-propanediol monocarbamate, a metabolite of felbamate

Article abstract of DOI:10.1021/op990198b

A simple, one-pot procedure for the preparation of 2-phenyl-1,3-propanediol monocarbamate (MCF) has been developed. This procedure represents the most efficient method for preparing MCF published to date, and it is amenable to the large-scale laboratory production of this biologically relevant metabolite of felbamate.

Full text of DOI:10.1021/op990198b

Organic Process Research & Development 2000, 4, 611−612
A Facile, One-Pot Procedure for the Preparation of 2-Phenyl-1,3-propanediol
Monocarbamate, a Metabolite of Felbamate
Thomas A. Miller,† Christine M. Dieckhaus, and Timothy L. Macdonald*
Columbia UniVersity, Department of Chemistry, 3000 Broadway, MC 3144, New York, New York 10027 and
Department of Chemistry, UniVersity of Virginia, McCormick Road, CharlottesVille, Virginia 22901
Abstract:
A simple, one-pot procedure for the preparation of 2-phenyl-
1,3-propanediol monocarbamate (MCF) has been developed.
This procedure represents the most efficient method for
preparing MCF published to date, and it is amenable to the
large-scale laboratory production of this biologically relevant
metabolite of felbamate.
Figure 1.
The anti-epileptic agent felbamate (Figure 1) has been
associated with the development of idiosyncratic adverse
drug reactions. The search for felbamate-replacement thera-
pies has led to the evaluation of agents structurally related
to felbamate, including the evaluation of metabolites of
felbamate.1 2-Phenyl-1,3-propanediol monocarbamate (Figure
1, MCF), a major metabolite of felbamate, has been shown
to possess activity similar to that of felbamate.2 Our work
Figure 2.
with MCF and MCF-derived agents required that this
Overall poor efficiency in the production of MCF by this
material be made available in significant quantities, with a
method led us to consider other approaches. An efficient
potential future need for this agent in kilogram quantities.
method for producing MCF was realized by the extension
Despite its relatively simple structure, no efficient syn-
of an approach characterized by the work of McDougal and
thesis of racemic MCF has been reported in the literature.
co-workers.5 By our method, which is summarized in Figure
Several methods have been developed; however, these
3, treatment of 2-phenyl-1,3-propanediol in THF successively
methods are characterized by a lack of efficiency, and as a
with NaH (1 equiv), after 2 h, a trialkylsilyl-chloride such
as TBDMS-Cl or TMS-Cl (1.1 equiv), then 1,1′-carbonyl-
diimidazole (1.5 to 2 equiv), and finally NH3 (l) followed
result, these existing protocols are not particularly amenable
to large-scale production.3 We sought to develop an efficient
and scaleable synthesis of MCF that would permit the
by silica gel chromatography affords the corresponding silyl-
laboratory-scale production of material to support our in vivo
protected MCF in g90% isolated yield for the TBDMS
studies of its pharmacology and physicochemical properties.
derivative.6
Our efforts in this regard have centered around the
This material is further treated with 10% methanolic HCl
to afford, after silica gel chromatography, MCF in g85%
overall yield. The elimination of chromatographic purifica-
desymmeterization of symmetric precursors to racemic MCF.
Initially, the formation of MCF via the cyclic carbonate of
2-phenyl-1,3-propanediol by the method of Sarel et al. was
tions was realized by the use of TMS-Cl in the silylation
assessed (Figure 2).4 Despite numerous attempts with varied
step. This has permitted the development of a “one-pot”
conditions, this method did not afford the requisite cyclic
procedure for the preparation of MCF from 2-phenyl-1,3-
species in quantities amenable to large-scale synthesis. It has
propanediol in g85% yield with purification via crystalliza-
been noted that this method is substrate-dependent and is
tion.
favored by 1,3-diols of increased substitution.4
† Current Address: Columbia University.
(1) Yang, J. T.; Adusumalli, V. E.; Wong, K. K.; Kucharczyk, N.; Sofia, R.
Experimental Section
All reactions were carried out under argon with magnetic
stirring unless otherwise noted. All solvents were distilled
from appropriate desiccant under nitrogen immediately prior
to use in reactions unless otherwise noted. All nuclear
magnetic resonance spectra were obtained with a General
D. Drug Metab. Dispos. 1991, 19, 1126-1138. Adusumalli, V. E.; Choi,
Y. M.; Romanyshyn, L. A.; Sparadoski, R. E.; Wichman, J. K.; Wong, K.
K.; Kucharczyk, N.; Sofia, R. D. Drug Metab. Dispos. 1993, 21, 710-
716.
(2) Smith, R. D.; Grzelak, M. E.; Coffin, V. L. Pharmacol. Biochem. BehaV.
1997, 58, 657-664. Morgan, B.; Bydlinsky, B.; Dodds, D. R. Tetrahedron
Asymmetry 1995, 6, 1765-1772.
(3) Choi, Y. M.; Kucharczyk, N.; Sofia, R. D. Tetrahedron 1986, 42, 6399-
6404. Thompson, C. D.; Kinter, M. T.; Macdonald, T. L. Chem. Res.
Toxicol. 1996, 9, 1225-1229.
(4) Sarel, S.; Pohoryles, L. A.; Ben-Shoshan, R. J. Org. Chem. 1959, 24, 1873-
1876.
(5) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org. Chem.
1986, 51, 3388.
(6) For alternative methods of preparation, see: Ihara, M.; Katsumata, A.; Setsu,
F.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1996, 61, 677.
10.1021/op990198b CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 10/24/2000
Vol. 4, No. 6, 2000 / Organic Process Research & Development
•
611

Figure 3.
Electric QE300 spectrometer at 300 MHz and chemical shifts
are reported in ppm. Elemental analysis was performed by
Atlantic Microlab, Inc., Norcross, GA. Melting points were
determined using a Thomas-Hoover UNI-MELT melting
point apparatus and are uncorrected. Analytical thin-layer
chromatography was performed on Merck silica gel 60 F-254
precoated plates (aluminum), and visualizations were effected
with phosphomolybdic acid in ethanol. Column chromatog-
raphy was performed on E. Merck silica 60 (230-400 mesh).
Representative Procedure. To 2-phenyl-1,3-propanediol7
(100.0 g, 0.675 mol) in THF (1000 mL) was added NaH
(95%, 17.0 g, 1.0 equiv) in five portions under argon with
magnetic stirring. After 2 h a voluminous precipitate had
formed, and TMS-Cl (77.0 g, 90.0 mL, 1.05 equiv) was
added via syringe. After 10 min the precipitate had dissolved,
and 1,1′-carbonyldiimidazole (164 g, 1.5 equiv) was added
to the solution. After the mixture was stirred for 2 h under
Ar(g), it was cooled to -78 °C and saturated with NH3. After
an additional 2 h of stirring, 20% HCl (200 mL) was added
to the reaction vessel in open air. After 1 h, ethyl ether (1000
mL) was added, and the organic layer was separated and
concentrated by rotary evaporation. After removal of the
volitiles was complete, the residue was crystallized by
dissolving it in a minimal amount of ethyl ether, and on
standing this afforded MCF (110 g, 86%) as a white
crystalline solid with purity >95% as judged by melting point
(71-72 °C), LC-MS traces, 1H NMR ((CD3)2SO) d 2.4 (bs,
1H), 3.1 (quin, 1H, J ) 6.2 Hz), 3.84 (d, 2H, J ) 6.2 Hz),
4.40 (d, 2H, J ) 6.2), 4.8 (bs, 2H), 7.3 (m, 5H), and
combustion analysis: Anal. Calcd for C10H13NO3: C, 61.53;
H, 6.71. Found: C, 61.37; H, 6.42.
Received for review October 11, 1999.
OP990198B
(7) Choi, Y. M.; Emblidge, R. W. J. Org. Chem. 1989, 54, 1198-2000.
612
•
Vol. 4, No. 6, 2000 / Organic Process Research & Development