Y. Torisawa et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6455–6458
(0.85 eq)
CO,
6457
4
Me
NH-CO
DMF (dry),
DBU
Me
NH-CO
Br
Me
O
N
OC
Me
Pd(OAc) / PPh3
2
heat: 125 ˚C, 3h
(3% SM remained)
1
Cl
2
(SM)
isolated yield: 80-85%
based on 4)
(
NMP, DBU, heat: 130˚C, 3h
Pd(OAc) / PPh
1
1
isolated yield: 78 %
(7% SM remained)
2
3
DMA, DBU, heat: 130 ˚C, 3h
Pd(OAc) / PPh
isolated yield: 80%
(8% SM remained)
2
3
Scheme 6. Aminocarbonylation with benzazepinone-3.
anhydrous conditions. Conversion of the aryl bromide 2
was most effectively attained in DMF, while almost
same conversion was feasible with N-methylpyrrolidone
References and notes
1. Miyazaki, T.; Fujiki, H.; Yamamura, Y.; Nakamura, S.;
Mori, T. Cardiovasc. Drug Rev. 2007, 25, 1.
. Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D. P. Chem.
Rev. 2007, 107, 2960.
(
NMP) and N,N-dimethylacetamide (DMA) (3 h at
30 °C).
2
1
3
. See as a general review (a) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Pergamon: Amster-
dam, 2000; (b) Mori, M. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.;
Wiley: New York, 2002; Vol. 2, pp 2313–2332.
We also attempted the blank experiment without ben-
zazepinone 4, which revealed the formation of small
amount of acid 3 and dimethylamide (by-product from
dimethylamine contained in DMF).
4
. Torisawa, Y.; Nishi, T.; Minamikawa, J. Bioorg. Med.
Chem. Lett 2000, 10, 2493, and references therein.
From the results obtained and shown in the Schemes,
we tentatively concluded that DMF was a preferable
5. Kubota, Y.; Hanaoka, T.; Takeuchi, K.; Sugi, Y. Synlett
994, 515.
1
(
convenient) solvent for this aminocarbonylation,
6
. See as an example of base selection: Atkins, R. J.; Banks,
A.; Bellingham, R. K.; Breen, G. F.; Carey, J. S.; Etridge,
S. K.; Hayes, J. F.; Hussain, N.; Morgan, D. O.; Oxley, P.;
Passey, S. C.; Walsgrove, T. C.; Wells, A. S. Org. Process
Res. Dev. 2003, 7, 663.
although small amounts of by-products were present
in the mixture with trace amount of bromide un-
changed. It is interesting to note that carbonylation
was slightly faster in DMF than in NMP and DMA,
and background reaction (as observed in blank exper-
iment) indicated the decomposition of DMF during
reaction under basic conditions. Decomposition of
DMF under Pd-catalyzed amination was reported
and thus DMF could work as a CO source in this
7
. Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org.
Chem. 2002, 67, 6232.
8. Experimental procedure: Substrates were well-dried and
placed in the reaction flask, while exchanging with Ar with
stirring before dissolving in the dried solvents (DMF etc.).
Thus, under tightly anhydrous conditions, a stirred
suspension of aryl bromide (2, 3.2 g) and benzazepinone
7
case.
(
4, 1.8 g) in DMF (6 mL)-DBU(2.5 mL) was charged with
CO at room temperature, before the quick addition of
Ph P (8 mol%) and Pd(OAc) (1.3 mol%) to the mixture.
Resulting mixture was then gradually heated at around
25 °C for ca. 3 h. Constant gas absorption was observed,
In summary, we have attained an efficient aminocarb-
onylation to the tolvaptan intermediate 1 in a single step
in reproducible yield. This is the notable example of
aminocarbonylation reaction, in which less reactive ben-
zazepinone 4 has been employed for the first time as a
3
2
1
while the mixture was maintained as orange colored
suspension. (In the case of DMF and NMP, a dark
mixture formed at this stage.) HPLC analysis (UV) at 3 h
indicated ca. 3 area % of SM remained along with the
product level reached to ca. 60 area %. After cooling to
room temperature, CO was removed from the reaction
flask by the aid of Ar bubbling. The mixture was then
diluted with AcOEt (150 mL)–NaOH aq (0.5 N, 50 mL)
with stirring. Aqueous layer was separated and organic
layer was washed well with dil HCl to remove DBU and
other polar materials. Crude extracts were further washed
with brine and neutral organic products were dried over
8
reaction partner.
Further improvement will be possible using other CO
9
,10
source.
Progress toward these convenient and safe
carbonylation processes is under active investigation in
our laboratories for the production of tolvaptan and
2
,11
other drug candidates.
Acknowledgments
MgSO
crude residue, which was purified by SiO
matography to afford the desired amide product (81–85%)
with 99.1% purity as judged by HPLC.
4
. Concentration of the dried solvents gave the
column chro-
We thank Dr. T. Kuroda at the research institute for
drug discovery at Otsuka Pharmaceutical Co., Ltd. for
helpful discussion.
2