Organic Process Research & Development 2006, 10, 1178−1183
Development of Large-Scale Preparations of Indole Derivatives: Evaluation of
Potential Thermal Hazards and Studies of Reaction Kinetics and Mechanisms
Atsushi Akao,*,† Nobuaki Nonoyama,† Toshiaki Mase,† and Nobuyoshi Yasuda‡
Process Research, Preclinical DeVelopment, Merck Research Laboratories, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan,
and Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, U.S.A.
Abstract:
ber-Batcho indole synthesis.6-8 Raney nickel is the most
common reducing reagent for this indole synthesis.6 As
mentioned above, our newly developed hydrogenation condi-
tions have been successfully applied to this reaction.5 To
select suitable reduction conditions for large-scale prepara-
tion, different conditions were evaluated by reaction calo-
rimetry to determine thermal hazards.
1.2. Potential Thermal Hazards EValuations. Raney Nickel
Vs Catalytic Hydrogenations. The Raney nickel reaction was
conducted by adding 3.9 equiv of hydrazine in EtOH at 52
°C. Chart 1 summarizes the calorimetry results from Raney
nickel reduction. The sum of yellow and orange areas under
the curve of heat flow in Chart 1 shows heat generation.
The timing of hydrazine addition is shown as arrows in Chart
1. Delay of heat generation (orange areas) was observed after
halting the additions of hydrazine. On the basis of the heat
generation from orange areas in Chart 1, the adiabatic
temperature at the delay areas was calculated to be 60 °C.
These data suggest that reaction temperature might exceed
the boiling temperature of EtOH without adequate cooling
capacity, creating potential risk for Raney nickel reduction
upon scale-up.
The proposed hydrogenation conditions also were evalu-
ated. Reaction was conducted at the same scale as the above
Raney nickel reaction in the presence of Rh/C doping with
the nickel additive under H2 at 30 °C. Chart 2 summarizes
the calorimetry results of the hydrogenation, which indicate
that the proposed hydrogenation conditions presented no
potential thermal hazards. Heat generation was minimal and
depended on agitation speed and hydrogen pressure. There-
fore, the reaction rate of the hydrogenation was determined
by diffusion rate of hydrogen into the reaction medium. The
reaction calorimetric studies clearly indicated that the heat
Hydrogenation of (E)-2-nitropyrrolidinostyrene in the presence
of the doped rhodium catalyst is safe, scalable, and highly
effective for the preparation of 6-benzyloxyindole. Reaction
kinetics with/without additives also were examined using in situ
IR for the first time. Results showed that the additives
decelerate the hydrogenolysis of benzyl ethers, while simulta-
neously accelerating the de-oxygenation of N-oxy-intermediates.
Introduction
The development of DNA topoisomerase I inhibitors as
cancer chemotherapy agents is an active area of research.1
An indolocarbazole drug candidate (1) has emerged because
of its potent cytotoxic activity against human cancer cells2
and its wide safety margin and is currently in clinical trials.
Bis-indolyl compound 2 is a key intermediate for the practical
and scalable synthesis of 13 (Figure 1). Bis-indolyl compound
2 is prepared from maleimide 3 and indole 4 under Steglich
conditions.4 For the Steglich conditions, the hydroxyl group
of 6-hydroxyindole must be protected, such as in 4.
Therefore, a scalable and practical synthesis of 4 was required
for the development of drug candidate 1.
We recently performed mild and high-yielding hydroge-
nations in the presence of Rh/C doped by additives, such as
Ni(NO3)2‚6H2O, Fe(OAc)2, or Co(acac)3, for the Leimgru-
ber-Batcho indole synthesis as shown in Scheme 1.5
Here, we report a large-scale procedure for the selective
preparation of 4 and the results of kinetic studies.
Results and Discussion
1. Choice of Reduction Methods for Large-Scale
Preparation. 1.1. Common Reaction Conditions for
Leimgruber-Batcho Indole Synthesis. Several different sets
of reaction conditions have been reported for the Leimgru-
(6) Batcho, A. D.; Leimgruber, W. Organic Syntheses; Wiley & Sons: New
York, 1990; Collect. Vol. 7, p 34.
(7) Metal iron and/or aluminum amalgam reductions are known. However, they
usually result in moderate yields and have the disadvantage of requiring
labor-intensive workup procedures to remove metal residues. In addition,
disposal of the waste metals can become an environmental problem.
Therefore, these conditions are suitable for large-scale syntheses. Reductions
using iron: (a) Kno¨lker, H.-J.; Hartmann, K. Synlett 1993, 755. (b)
Sinhababu, A. K.; Borchardt, R. T. J. Heterocycl. Chem. 1988, 25, 1155.
Reductions using aluminum amalgam: Toste, F. D.; Still, I. W. J. Org.
Prep. Proced. Int. 1995, 27, 576.
(8) Catalytic hydrogenation using common catalysts are known. In general, these
reactions result in high yields but can have low chemoselectivity. (a) Tamara,
K., Ed. Hannoubetsu Jitsuyou Shokubai; Kagaku Kougyou Sha Inc.: Tokyo,
1970. (b) Augastine, R. L. Catalytic Hydrogenation; Marcel Dekker Inc.:
New York, 1965. (c) Freifelder, M. Practical Catalytic Hydrogenation; John
Wiley & Sons, Inc.: New York, 1971. (d) Arnold, M. R. Ind. Eng. Chem.
1956, 48, 1629. (e) Ashmore, P. G. Catalysis and Inhibition of Chemical
Reactions; Butterworth: Woburn, MA, 1969.
* To whom correspondence should be addressed. Telephone: +81-29-877-
† Process Research, Preclinical Development, Merck Research Laboratories.
‡ Department of Process Research, Merck Research Laboratories.
(1) Long, B. H.; Balasubramanian, B. N. Expert Opin. Ther. Pat. 2000, 10,
635.
(2) Ohkubo, M.; Nishimura, T.; Honma, T.; Nishimura, I.; Ito, S.; Yoshinari,
T.; Arakawa, H.; Suda, H.; Morishima, H.; Nishimura, S. Bioorg. Med.
Chem. Lett. 1999, 9, 3307.
(3) Akao, A.; Hiraga, S.; Iida, T.; Kamatani, A.; Kawasaki, M.; Mase, T.;
Nemoto, T.; Satake, N.; Weissman, S. A.; Tschaen, D. M.; Rossen, K.;
Petrillo, D.; Reamer, R. A.; Volante, R. P. Tetrahedron 2001, 57, 8917.
(4) Steglich, W.; Steffan, B.; Kopanski, L.; Eckhardt, G. Angew. Chem., Int.
Ed. Engl. 1980, 19, 459.
(5) Akao, A.; Sato, K.; Nonoyama, N.; Mase, T.; Yasuda, N. Tetrahedron Lett.
2006, 47, 969.
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Vol. 10, No. 6, 2006 / Organic Process Research & Development
10.1021/op060150f CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/24/2006