Organic Process Research & Development
TECHNICAL NOTE
reactor (through subsurface sparging tubes in the amination
’ REFERENCES
vessel) while maintaining 25-35 °C with jacket cooling (5-
(
1) (a) Somei, M.; Natsume, M. Tetrahedron Lett. 1974, 461. (b)
1
0 °C). The feeds were stopped after 90 min, at which time a total
Somei, M.; Matsubara, M.; Kanda, Y.; Natsume, M. Chem. Pharm. Bull.
1978, 26 (8), 2522.
(2) Weiberth, F. J.; Lee, G. E.; Hanna, R. G.; Mueller-Lehar, J.;
Dubberke, S.; Utz, R. U.S. Patent 7,112,682, September 26, 2006 (CAN
of 43.9 kg of the KOtBu solution (4.1 equiv) and 42.0 kg of the
HOSA solution (2.1 equiv) had been charged, and a 97 A%
conversion to 3b was achieved. The workup was performed in
two portions. One half of the batch was transferred to a 30-gal
reactor that contained cold water (48 L) and toluene (12 L).
After stirring for 10 min at 20-25 °C, the phases were separated.
The aqueous phase was extracted with toluene (3 Â 12 L). The
combined organic phase was washed with water (2 Â 16 L). The
other half of the batch was worked up similarly. The organic
phases from each portion of the workup were combined and
concentrated (60 °C, <50 mbar) to give 5.2 kg (4.5 kg of product
corrected for 3.4 wt % toluene and 6.9 wt % NMP as determined
by NMR and 96 A% HPLC purity, 89.7% yield) of 3b as an oil
that solidified upon standing. Similarly, a second amination was
1
42:411224).
3) Indoles are not sufficiently nucleophilic to react directly
with HOSA.
(
(
4) No desired product would be expected if solutions of the
incompatible reagents HOSA and KOtBu were mixed prior to the
addition of indole.
(
5) Hynes, J., Jr.; Doubleday, W. W.; Dyckman, A. J.; Godfrey, J. D.,
Jr.; Grosso, J. A.; Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69, 1368.
6) (a) The pK of the N-H proton in indole is reported to be
(
a
∼17. See: Remers, W. A. Properties and Reactions of Indoles, Iso-
indoles, and Their Hydrogenated Derivatives. In Indoles, Part I;
Houlihan, W. J., Ed.; The Chemistry of Heterocyclic Compounds;
Wiley & Sons, Inc.: New York, 1972; p 14. (b) The pK of t-BuOH is
a
commonly reported to be within the range of 17-19, depending on the
specific literature source.
1
performed on the same scale to give 3b in 91.1% yield. H NMR
(
7
1
300 MHz, CDCl , δ): 2.28 (s, 3H), 4.45 (br s, 2H), 6.85 (s, 1H),
3
.09 (apparent t, J = 7.5 Hz, 1H), 7.20 (apparent t, J = 7.5 Hz,
13
(7) Conversions to 3a were typically 60-68 A% when only 1.0 equiv
of HOSA was dispensed simultaneously with 2.0 equiv of KOtBu.
H), 7.28 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H); C NMR
(
1
CDCl , δ): 9.4, 108.0, 108.1, 118.8, 118.9, 121.7, 126.6,
3
(8) Dipolar aprotic solvents were preferred because they solubilized
27.1, 136.9.
-Benzyloxy-1H-indol-1-amine (3c). A solution of HOSA
both HOSA and KOtBu. NMP was especially preferred because it was
also suitable for downstream chemistry (telescoping).
5
(
(
5.3 kg, 5.1 kg corrected for purity, 45.1 mol, 2.15 equiv) in NMP
19.1 kg) was prepared as described above and chilled to 0-5 °C.
(9) The N-amination was a very fast reaction (e.g., 1 min stirring was
sufficient to provide representative conversion assays after feeds were
momentarily interrupted for in-process sampling). Consequently, this
latter charging regimen has shown potential to be adapted into a flow
reaction, although the advantage may be limited because reagent
solutions will need to be prepared freshly in batch mode just prior to
processing (see ref 16), and an amination vessel would still be needed to
collect the product stream.
A second solution was prepared from KOtBu (10.1 kg corrected
for 95% purity, 90.0 mol, 4.3 equiv) and NMP (19.3 kg). An
amination vessel was charged with benzyloxyindole (5.0 kg, 4.7
kg corrected for 94% purity, 21.0 mol), NMP (15.5 kg), and an
initial charge of the KOtBu/NMP solution (0.37 kg, 0.05 equiv).
The HOSA/NMP solution and the remaining KOtBu/NMP
solution were then simultaneously and proportionally metered
(
10) As determined by HPLC assay. The balance of material was
mostly unreacted indole.
11) In this discussion, XP refers to Class 1, Division 1, Group C/D
processing environments.
12) Major components: Bran & Luebbe duplex metering plunger
(0.142 kg/min and 0.172 kg/min, respectively) into the amina-
(
tion vessel over a period of 172 min while maintaining a reaction
temperature of 14-29 °C with jacket cooling (10 °C) to afford a
solution containing a 98.6:1.4 mixture (HPLC assay) of 3c:1c.
The reaction mixture was then added over a period of 16 min to
(
pump model N-P32 with pulsation dampener SG-TW-25 and back-
pressure valve 14010-2300; Micro Motion mass flow sensor
D12H205SU (1/8-in tubes); Micro Motion transmitter model
RFT9739E1SU; Micro Motion flow monitoring device model
FMS1NA0EA.
1
16 L of water while maintaining a temperature of 13-26 °C.
The resulting suspension was cooled to 0-5 °C and filtered. The
filter cake was rinsed with water (2 Â 21 L) and then was
partitioned with n-butyl acetate (63 L) and water (8.5 L). The
resulting mixture was filtered and rinsed with n-butyl acetate (10
L). The organic phase of the filtrate was separated, washed with
(13) All materials should be handled while minimizing exposure and
while wearing proper protective equipment, most importantly when
handling HOSA and KOtBu, both of which can cause burns on skin and
in the eyes and are extremely destructive to mucous membranes and the
upper respiratory tract.
water (4.2 L), and dried over K CO (3 kg) and then was filtered,
2
3
concentrated under reduced pressure, and air-dried to give 4.7 kg
(14) All materials, including NMP, were accurately preweighed.
of 3c as a brown solid (3.9 kg by wt/wt HPLC assay, 77.4%
(15) HOSA was charged in 3 portions over about 15 min to
1
yield). H NMR (300 MHz, CDCl , δ): 4.70 (br s, 2H), 5.09 (s,
minimize formation of clumps of the solid that were then difficult to
3
2
H), 6.25-6.37 (m, 1H), 6.93-7.56 (m, 9H).
dissolve.
(16) Iodometric titrations established that HOSA dissolved in NMP
solutions was stable for 18 h at e10 °C and 1 h at 35 °C. At 40 °C, the
activity of HOSA dissolved in NMP decreased from 95% to 88% after 1
h.
(17) Alternatively, a separately weighed charge of KOtBu could be
added directly into the amination reactor.
’
AUTHOR INFORMATION
Corresponding Author
franz.weiberth@sanofi-aventis.com
Notes
Member of Chemical Development, Hoechst Marion Roussel,
(18) This failed batch was salvaged by isolating the product
§
(extractive workup), then reprocessing the resulting mixture of 3c:1c
by treatment with additional HOSA/NMP and KOtBu/NMP in a
simultaneous manner to give a 98 A% conversion to 3c.
Inc., Bridgewater, NJ, at the time some of thisworkwas conducted.
(
19) In later campaigns, it was found that a precharge of 0.07-0.10
’
ACKNOWLEDGMENT
equiv of KOtBu resulted in more robust performance.
We are grateful to the many colleagues within our organization
who provided pilot-plant, technical and operations support.
(20) The sparging tubes were fabricated from 3/8-in SS tubing by
drilling a series of twenty 1/16-in. diameter holes in the submersed and
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08
dx.doi.org/10.1021/op100330h |Org. Process Res. Dev. 2011, 15, 704–709