Development of the Hofmann rearrangement of Nα-tosylasparagine through calorimetric and NMR analysis

Full text of DOI:10.1021/jo980799l

J . Org. Chem. 1998, 63, 9533-9534
9533
Develop m en t of th e Hofm a n n
Rea r r a n gem en t of Nr-Tosyla sp a r a gin e
th r ou gh Ca lor im etr ic a n d NMR An a lysis
J oseph S. Amato,* Carl Bagner, Raymond J . Cvetovich,
Sue Gomolka, Frederick W. Hartner, J r., and
Robert Reamer
Departments of Process Research and Chemical Engineering
Research & Development, Merck Research Laboratories,
Rahway, New J ersey 07065
Received April 28, 1998
F igu r e 1. Fibrinogen receptor antagonist 1.
In tr od u ction
Looking to unravel the critical reaction parameters led
us to an examination of the calorimetry during the
reaction. Reactions were studied in a Mettler RC1 unit6
in which the heat flows were measured, samples were
withdrawn after each thermal event, and 1H and 13C
NMR measurements were performed. A cold solution of
sodium hypobromite (prepared by the addition of 1 equiv
of bromine to 1 equiv of aqueous sodium hydroxide) was
added to a cold solution of asparagine in aqueous sodium
hydroxide in the RC1 unit during which a -23.5 kcal/
mol heat flow was measured. A sample was withdrawn
to record the NMR. This sample gave spectra consistent
with expected N-bromo intermediate 3 but also consistent
with initial bromination of the tosylamide nitrogen
(which could transfer to the primary amide). After the
reaction was stirred at 0 °C for 15 min, external heat
was supplied from the jacket of the reactor, and the
calories of heat were measured during the heating. At
28 °C an exothermic event was observed in which a -64.7
kcal/mol heat flow was measured. The reaction temper-
ature rose to 35 °C while heat was removed from the
jacket of the reactor. After this thermal event a sample
was withdrawn. Examination by 1H and 13C NMR found
complete conversion of N-bromo intermediate 3 to the
imidazolidine derivative 4 via rapid intramolecular trap-
ping of the expected isocyanate intermediate. Imidazo-
lidine 4 can be isolated as a crystalline solid at this point
by cooling and acidifying with aqueous HCl.7
Recently, we had need to prepare kilogram quantities
of 2-(S)-(tosylamino)-â-alanine (6), an important inter-
mediate in the synthesis of potent fibrinogen receptor
antagonist 11 (Figure 1). This non-peptide molecule is
an active fibrinogen receptor antagonist that offers a
promising approach to the treatment of vascular diseases
through a mechanism of control of platelet aggregation.2
NR-Tosylaminoalanine (6) was prepared via the Hof-
mann rearrangement of NR-tosylasparagine. Although
this reaction is described in the literature,3 in our hands
the reaction was inconsistent, with yields oscillating
between 10 and 70%. Herein, we report a delineation of
the sequence of intermediates involved in the reaction
of sodium hypobromite with NR-tosylasparagine in aque-
ous sodium hydroxide. This study has resulted in an
understanding of the sequence of reaction intermediates
which has allowed greater control of the reaction param-
eters to achieve reproducibly high isolated yields (70%)
of NR-tosylaminoalanine (6) on scales ranging from 1 g
to 3 kg.
Resu lts a n d Discu ssion
The Hofmann rearrangement of NR-tosylasparagine (2)
has been described as a reaction that requires utmost
care to achieve the reported yield, and efforts to improve
the yield of the rearrangement were unsuccessful.4,5 We
observed similar problems with the reproducibility of this
venerable reaction with NR-tosylasparagine (2) when the
rearrangement was run on a kilogram scale, with sig-
nificant variability in yield (10-70%) and no discernible
differences noted in the procedure that was followed.
Heat was again supplied to the reaction from the jacket
of the reactor, and at 50 °C another thermal event was
observed, in which -13.5 kcal/mol heat flow was mea-
sured. NMR analysis of the reaction after this thermal
event was consistent with carbamic acid 5. Further
heating of the reaction to 70 °C produced a final thermal
event, in which -17.8 kcal/mol heat flow was measured.
NMR and HPLC analysis, with comparison with known
(1) Askew, B. C.; McIntyre, C. J .; Hunt, C. A.; Claremon, D. A.;
Gould, R.; Lynch, R. J .; Armstrong, D. J . Bioorg. Med. Chem. Lett. 1995,
5, 475.
(6) Mettler Instrument Co.
(2) (a) Ojima, I.; Charkravarty, S.; Dong, Q. Bioorg. Med. Chem.
1995, 3, 337. (b) Schror, K. Drugs 1995, 50, 7. (c) Cook, N. S.; Kottirsh,
G.; Zerwes, H.-G. Drugs Future 1994, 19, 135. (d) Nichols, A. J .; Vasko,
J . A.; Koster, P. F.; Valocik, R. E.; Samenen, J . M. In Cellular
Adhesion: Molecular Definition to Therapeutic Potential; Metcalf, B.
W., Dalton, B. J ., Poste, G., Eds.; Plenum Press: New York, 1994; pp
213-237.
(3) (a) Rudinger, J .; Poduska, K.; Zaoral, M. Collect. Czechoslov.
Chem. Commun. 1960, 25, 2022. (b) Hayashi, K.; Nunami, K.; Kato,
J .; Yoneda, N.; Kubo, M.; Ochiai, T.; Ishida, R. J . Med. Chem. 1989,
32, 289.
(7) Imidazolidine 4 was isolated from reaction mixtures after
warming to 40 °C: 1H NMR (500.13 MHz, DMSO-d6) δ 13.4 (br s, 1H),
7.86 (m, 2H), 7.66 (s, 1H), 7.41 (m, 2H), 4.86 (dd, J ) 10.3, 4.8, 1H),
3.71 (t, J ) 10.3, 1H), 3.26 (dd, J ) 10.3, 4.8, 1H), 2.40 (s, 3H); 13C
NMR (125.76 MHz, DMSO-d6) δ 171.3, 154.0, 144.2, 135.9, 129.2, 127.9,
56.3, 40.8, 20.9. In-situ data (referenced to external dioxane): 1H NMR
(399.87 MHz, NaOD) δ 7.36 (d, J ) 8.0, 2H), 6.93 (d, J ) 8.0, 2H),
3.98 (dd, J ) 10.4, 6.8, 1H), 3.14 (dd, J ) 12.1, 10.4, 1H), 2.77 (dd, J
) 12.1, 6.8, 1H), 1.92 (s, 3H); 13C NMR (100.55 MHz, NaOD) δ 180.6,
160.9, 145.9, 134.6, 130.5, 127.7, 62.5, 49.9, 21.5. Anal. Calcd for
C
11H12N2SO5: C, 46.47; H, 4.25; S, 11.28; N, 9.85. Found: C, 46.16;
(4) Aders, K.; Vesterager, E. Acta Chem. Scand. 1960, 14, 961.
(5) Shiba, T.; Koda A.; Kusamato, S.; Kanefko, T. Bull. Chem. Soc.
J pn. 1968, 41, 2748.
H, 4.11; S, 11.30; N, 9.68. This intermediate was shown to proceed to
product in NMR experiments consistent with the original NMR
experiments.
10.1021/jo980799l CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/21/1998

9534 J . Org. Chem., Vol. 63, No. 25, 1998
Notes
Sch em e 1. In ter m ed ia tes a n d P r od u cts of th e
Hofm a n n Rea r r a n gem en t of (l)-Asp a r a gin e
hypobromite was added to sodium asparaginate at <10
°C to give rapid N-bromination as determined by HPLC
and NMR assays. Upon complete addition of sodium
hypobromite, the reaction is heated to 40 °C, heating is
suspended at 40 °C, but the heat generated during this
exothermic reaction brings the temperature of the mix-
ture to 50-55 °C. When this exothermic event is over
complete consumption of N-bromo intermediate 3 has
occurred to form imidazolidine 4. When the internal
temperature begins to fall, the reaction is heated to 70
°C in order to hydrolyze imidazolidine 4 and decarboxy-
late carbamate 5, thus completing the sequence of
reactions to produce 2-(S)-(tosylamino)-â-alanine (6) as
the sodium salt.
The understanding of the discrete intermediates, exo-
thermic events, and sensitivity of intermediates and
product to reagents and to each other in the Hofmann
rearrangement of NR-tosyl-(l)-asparagine led to a process
that gave 2-(S)-(tosylamino)-â-alanine (6) on multikilo-
gram scale in consistent 90% in-process yield and 70%
isolated yield (Scheme 1).
samples, allowed identification of sodium NR-tosylami-
noalanine (6) as the major product, and tosylamide (8)
as a minor component.
The overall experimental heat of reaction was -116.3
kcal/mol, which was consistent with a calculated value
from the heats of formations of the products and reac-
tants from a model reaction.8
Exp er im en ta l Section
2-(S)-(Tosyla m in o)-â-a la n in e3 (6). Sodium hydroxide (3.48
kg, 87.0 mol) was dissolved in water (22 L), and the solution
was cooled to 0 °C. Bromine (0.63 L, 11.8 mol) was added over
30 min while the temperature was maintained at 0-10 °C. In a
second vessel, NR-tosylasparagine (2.86 kg, 9.48 mol) was added
in portions to a solution of NaOH (0.8 kg, 20.0 mol) in water
(7.2 L) kept cold at 0-10 °C. The solution was cooled to 0 °C,
and the sodium hypobromite solution was added over 10 min
while maintaining a temperature <10 °C. After the addition,
the resulting yellow solution was aged for 15 min at 10-15 °C,
and then heated to 40 °C within 30 min. Heating was suspended
and the reaction temperature was allowed to increase to 50 °C
over 20 min due to the exothermic reaction. When the internal
temperature dropped to 45 °C, the reaction solution was heated
to 70 °C over 20 min and kept at 70 °C for 10 min. HPLC
analysis measured a 90% solution yield of 2-(S)-(tosylamino)-â-
alanine (6). The reaction was cooled to 10-15 °C, and with
vigorous stirring the pH of the mixture was adjusted to 7 by
the addition of concentrated hydrochloric acid (4 L), whereupon
the product precipitated. The mixture was stirred for 20 min at
15 °C, and the product was filtered. The cake was slurry washed
with water (2 × 8 L) and then displacement washed with water
(8 L). The product was dried with a nitrogen stream at 20 °C
affording 1.67 kg of 2-(S)-(tosylamino)-â-alanine (6) in 70%
isolated yield.
With the identification of critical reaction intermedi-
ates, our attention turned to a study of the stability of
reaction intermediates, reagents, and product at each
stage of the reaction. Heating of NR-tosylasparagine (2)
with sodium hydroxide produced aspartic acid sodium
salt (7). NR-tosylaminoalanine (6) was rapidly decom-
posed by either sodium hypobromite or Nγ-bromoaspar-
agine 3 to produce tosylamide (8) along with formic acid.
Adding N-bromo-intermediate 3 dropwise to hot sodium
hydroxide led to product mixtures that were similar to
the reaction seen when the product was exposed to Nγ-
bromo-NR-tosylasparagine 3. It became evident from
these observations that the key to obtaining a high yield
in the rearrangement was to ensure that all of interme-
diate 3 was consumed prior to formation of any product
and that excess hypobromite be avoided.
The calorimetric and NMR data indicated that the
sequence of reactions could be separated by control of
temperature and heating time cycles and that this control
was essential to achieve good reproducible yield in this
Hofmann reaction. On the basis of these data, a proce-
dure was developed with discrete heating stages. Sodium
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compound 4 (2 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of this journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(8) The value of the heat of formation of 6 was estimated on the
basis of the heat of formation of 3-aminopropionic acid (-138 kcal/
mol) plus the heat of formation of a secondary amine from hydrocarbon
(-3.8 kcal/mol).
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