Development of a large scale asymmetric synthesis of vanilloid receptor (TRPV1) antagonist ABT-102

Article abstract of DOI:10.1021/op060228s

A highly efficient asymmetric synthesis of TRPV1 antagonist ABT-102 was developed and successfully demonstrated on a multi-kilogram scale. This process incorporates a new asymmetric synthesis of (R)-tert-butylaminoindan, which is based on a chiral auxiliary induced diastereoselective reduction of its iminoindan precursor.

Full text of DOI:10.1021/op060228s

Organic Process Research & Development 2007, 11, 578−584
Development of a Large Scale Asymmetric Synthesis of Vanilloid Receptor
(TRPV1) Antagonist ABT-102
Kirill Lukin,* Margaret C. Hsu, Gilles Chambournier,† Brian Kotecki, C. J. Venkatramani, and M. Robert Leanna
GPRD Process Chemistry, Abbott Laboratories, R-13, North Chicago, Illinois 60064-6291, U.S.A.
Scheme 1. General synthesis of indazyl ureas 1
Abstract:
A highly efficient asymmetric synthesis of TRPV1 antagonist
ABT-102 was developed and successfully demonstrated on a
multi-kilogram scale. This process incorporates a new asym-
metric synthesis of (R)-tert-butylaminoindan, which is based on
a chiral auxiliary induced diastereoselective reduction of its
iminoindan precursor.
5. In those cases, when the benzyl amine counterpart had a
chiral center (e.g., 5, R1 * H) the separation of the resulting
racemic ureas into the two pure enantiomers was achieved
by a preparative chiral HPLC method.
In order to develop a reliable and robust large scale
synthesis of enantiopure compound 2, we decided to utilize
the convenience of the convergent synthetic approach
outlined in Scheme 1 while identifying and incorporating
into the process an asymmetric synthesis of the R-enantiomer
of 5-tert-butylaminoindan 6.
Introduction
Vanilloid receptor TRPV1 has been identified as a
promising target for the development of innovative medicines
designed for treatment of chronic pain.1 The available
experimental data suggest that compounds targeting the
TRPV1 receptor could provide pain relief without causing
such side effects as addiction.1 Subsequent efforts identified
the indazole based ureas 1 as a class of potent TRPV1
antagonists.2
Further elaboration of the above approach resulted in an
efficient asymmetric synthesis of ABT-102 suitable for multi-
kilogram scale preparations. The details of this work are
discussed in this manuscript.
Further SAR optimization of these leads resulted in the
discovery of ABT-102 (2) which possessed an excellent set
of properties suitable for its further development as a clinical
candidate.3 In order to support this clinical program the
process chemistry group was challenged to develop a robust
and scalable synthesis of enantiopure compound 2.
The original general approach for the preparation of
indazyl ureas 1, including ABT-102 (2), is outlined in
Scheme 1.2
Results and Discussion
1. Preparation of 1-N-Protected 4-Aminoindazole 3.
Scheme 2 outlines a general synthetic approach to 1-N-
protected aminoindazoles reported in the literature.2,4 Fol-
lowing this approach, nitroindazole 7 was prepared via
diazotation/cyclization of the corresponding nitrotoluidine 8,
protection of the indazole nitrogen using a suitable group,
and reduction of the nitro group to amine 9.
This synthesis is based on the preparation of an ap-
propriately protected 4-amino substituted indazole derivative
3, its conversion into isocyanate intermediate 4, followed
by coupling of the isocyanate with the desired benzylamine
Scheme 2. General synthesis of aminoindazoles 9
* To whom correspondence should be addressed. E-mail: kirill.lukin@
abbott.com.
† Current address: Cayman Chemical Company, Ann Arbor, Michigan.
(1) For a review, see: Szallasi, A.; Appendino, G. J. Med. Chem. 2004, 47,
2717.
(2) Drizin, I.; Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.;
Perner, R. J.; Didomenico, S.; Koenig, J. R.; Turner, S. C.; Jinkerson, T.
K.; Brown, B. S.; Keddy, R. G.; McDonald, H.A.; Honore, P.; Wismer, C.
T.; Marsh, K. C.; Wetter, J. M.; Polakowski, J. S.; Segreti, J. A.; Jarvis, M.
F.; Faltynek, C. R.; Lee, C.-H. Bioorg. Med. Chem. 2006, 14, 4740.
(3) Gomtsyan, A.; Bayburt, E. K.; Koenig, J. R.; Lee, C.-H. U.S. Pat. Appl.
2004254188, Dec 16, 2004.
(4) (a) Porter, H. D.; Peterson, W. D. Org. Synth. 1940, 20, 73. (b) Benchidmi,
M.; Bouchet, P.; Lazaro, R. J. Heterocycl. Chem. 1979, 16, 1599.
578
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10.1021/op060228s CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/23/2007

Although this synthetic sequence could be easily repro-
duced on a gram scale, several issues have been uncovered
during the development of a kilogram scale process. Specif-
ically, step 1 nitroindazole 104 formation was particularly
challenging.
The next synthetic step, nitro group reduction, was initially
conducted under standard hydrogenation conditions utilizing
palladium on carbon as a catalyst and methanol as a solvent
(eq 2). However, during the subsequent process optimization,
it was found that up to 30% of aminoindazole 3 could be
deprotected under the reaction conditions in alcoholic
solvents. The problem was resolved by changing the reaction
solvent to THF or ethyl acetate. Upon catalyst filtration,
aminoindazole 32 was isolated from the reaction mixture in
the form of a stable hydrochloride salt via HCl addition.
Overall, the three-step synthesis gave the indazole 3
building block in 77% yield on a kilogram scale.
2. Asymmetric Synthesis of R-(tert-Butylindanyl)amine
6. Preparation of the chiral aminoindan 6 was investigated
next. Our synthetic approach to 6 was based on the utilization
of 5-tert-butylindanone 146 as a starting material. We thought
that this ketone could be converted into chiral amine 6 either
through the preparation of the corresponding racemic amine
6-rac (eq 3), followed by its resolution, or, hopefully more
efficiently, via a direct asymmetric synthesis.
Thus, according to the literature procedure,4 a fast, one
portion addition of the sodium nitrite solution to the mixture
of nitrotoluidine 11 and acetic acid was required in order to
obtain acceptable yields of 10 (eq 1). A slower addition of
the sodium nitrite solution resulted in a massive precipitation
of an unknown compound and incomplete reaction. However,
the desired fast addition of the nitrite reagent produced a
large exotherm (58 °C adiabatic temperature increase), which
was very difficult to control on a scale. As a first step to
resolve this issue, we isolated the intermediate precipitate
and identified its structure as triazene 12.5 Then it was found
that the triazene formation was reversible and that it could
be converted into nitroindazole 10 by the addition of excess
sodium nitrite (eq 1). Based on these observations we were
able to develop a new protocol for the preparation of 10
which included a slow addition (over 1 h period) of the
sodium nitrite solution to the preheated reaction mixture at
50 °C. This process provides good control of the exotherm
and prevents the intermediate triazene precipitation. The
optimized synthesis was reproducibly conducted on a
kilogram scale and gave nitroindazole 10 in 95% isolated
yield upon its precipitation from the reaction mixture with
water.
A large scale, robust preparation of indanone 14 was
subsequently developed to support the synthetic efforts
toward chiral amine 6. The synthesis of 5-tert-butylindanone
14 was previously reported in the literature,6 as part of a
general methodology for the preparation of indanones, as
shown in eq 4.7
For the second step of the synthesis, nitroindazole
protection, we selected the methoxycarbonyl group because
it could be selectively installed on the 1-N position, provided
sufficient stability of intermediates throughout the process,
and was easy to remove. The installation of the protection
group was consequently achieved by the addition of methyl
chloroformate to a solution of nitroindazole 10 in DMF in
the presence of DBU as a base (eq 2). Resulting compound
13 was then precipitated from the reaction mixture by water
addition. On a kilogram scale intermediate 13 was repro-
ducibly isolated in 88% yield.
This synthesis includes Fridel-Crafts acylation of tert-
butylbenzene, followed by a Nazarov type cyclization of the
intermediate â-chloroketone 16 in concd sulfuric acid.7 While
the first step of this synthesis was easily scalable and
produced intermediate 16 in >90% yield, the following
cyclization step required substantial optimization prior to
scaleup. Thus, small-scale cyclization reactions had to be
conducted at a fairly high dilution (0.2 M) using concd
(6) Hannig, E. Pharmazie 1965, 20, 762.
(7) For example, see: Bartmann, W.; Konz, E.; Rueger, W. J. Heterocycl. Chem.
1987, 677.
(5) Benes, J.; Beranek, V.; Zimprich, J.; Vetesnik, P. Coll. Czech. Chem.
Commun. 1977, 42, 702.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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sulfuric acid as a solvent to prevent polymerization of the
intermediate enone 17. The subsequent workup of these
reactions with water created a very large exotherm and
required unacceptably high process volumes. With optimiza-
tion, this reaction was conducted at higher concentrations
(0.7 M), and the polymerization of 17 was minimized by
adding chloroketone 16 to preheated sulfuric acid at 90 °C
at a rate comparable to the rate of enone 17 cyclization (see
Experimental Section for details). This method of the reagent
addition maintained a low concentration of the enone
intermediate in the mixture throughout the synthesis and,
thus, prevented its polymerization.
Under the optimized conditions the synthesis of tert-
butylindanone was successfully conducted on a kilogram
scale and gave an 83% assayed yield of indanone 14 for the
two-step sequence.
Resolution of Racemic Amine 6-rac. The possibility of
resolving racemic amine 6-rac was examined initially as a
most straightforward approach to chiral amine 6. Racemic
6-rac was prepared from indanone 14 via the formation of
oxime 15, followed by hydrogenation in the presence of
Raney nickel and ammonia, as shown in eq 3.
To resolve the racemate we utilized a method previously
reported in the literature for the resolution of the unsubsti-
tuted analogue of 6, i.e., 1-aminoindan.8 Following this
procedure, a methanolic solution of 5-tert-butyl-aminoindan
(6-rac, 1 equiv) and N-acetyl-L-leucine (0.5 equiv) were
combined to give the (S)-enantiomer as a crystalline salt.
This first crop of this salt was isolated in 30% yield and
∼80% ee chiral purity.
diastereoselective reduction of chiral iminoindan 18, was
selected for a kilogram scale process development as the most
practical and efficient.
Diastereoselective Reduction of Chiral Iminoindan 18.
The use of enantiopure R-methylbenzylamines 19 as chiral
auxiliaries in stereoselective reductive amination reactions
(eq 9) has been well documented.14
6-rac N-Ac-D-leucine8 6 × N-Ac-D-leucine
(5)
0.5 equiv
The preparation of the desired (R)-enantiomer 6 was then
accomplished in a similar manner using N-acetyl-D-leucine
(eq 5). The latter resolving agent was not commercially avail-
able but could be easily prepared by N-acetylation of
D-leucine with acetic anhydride.9 Upon further optimization
of the resolution parameters, we were able to isolate the
corresponding salt of 6 with >97% ee chiral purity in 18%
yield. This resolution approach was used in the preparation
of the first gram size batches of 6. However, the method was
unsuitable for a kilogram scale process due to the high cost of
unnatural D-leucine and less than desired resolution efficiency.
Our research efforts were consequently shifted to a chiral
synthesis of 6. The two primary approaches were (1)
asymmetric reduction of indanone 14 followed by stereose-
lective amination (eq 6) and (2) auxiliary induced diaste-
reoselective reduction of iminoindans, as shown in eqs 7 and
8.
According to this approach, chiral imine intermediate 20,
prepared from corresponding ketone and amine auxiliary, is
(12) Utilizing Ellman’s methodology13 amine 6 (92 % ee) was prepared in 21%
yield for a three-step sequence including conversion of 14 into an (R)-(+)-
tert-butylsulfinimide derivative, followed by diastereoselective reduction
with NaBH4 and the auxiliary cleavage with concd HCl .
(13) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 1278.
(14) (a) Bringmann, G.; Geisler J.-P. Tetrahedron Lett. 1989, 30, 317. (b)
Bringmann, G. B.; Kunkel, G; Geuder, T. Synlett 1990, 253. (c) Bringmann,
G.; Geisler, J.-P. J. Fluorine Chem. 1990, 49, 67. (d) Bringmann, G.; Geisler,
J.-P.; Geuder, T.; Ku¨enkel, G.; Kinzinger, L. Liebigs Ann. Chem. 1990,
795. (e) Kanai, M.; Yasumoto, M.; Kuriyama, Y.; Inomiya, K.; Katsuhara,
Y.; Higashiyama, K.; Ishii, A. Org. Lett. 2003, 5, 1007. (f) Gutman, A. L.;
Etinger, M.; Nisnevich, G.; Polyak, F. Tetrahedron: Asymmetry 1998, 9,
4369. (g) Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.;
Fortunak, J. M.; Giangiordano, M.; Haley, J. J.; Kamholz, K.; Li, H.-Y.;
Ma, P.; Nugent, W. A.; Parsons, R. L.; Sheeran, P. J.; Silverman, C. E.;
Waltermire, R. E.; Wood, C. C. Org. Process Res. DeV. 2002, 6, 54.
Although all three explored approaches ultimately gave
desired chiral amine 6,10-13 only the latter one, based on
(8) Smith, H. E.; Willis, T. C. Tetrahedron 1970, 26, 107.
(9) DeWitt, H. D.; Ingersoll, A. W. J. Am. Chem. Soc. 1951, 73, 3359.
(10) A three-step sequence including asymmetric reduction of 14 with (R)-CBS-
11
BH3 and azidation of the resulting alcohol with DPPA, followed by the
azide reduction with LAH, gave 6 in a 66% overall yield and 79% ee chiral
purity.
(11) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll,
J. D.; Corley, E. G.; Grabowski, E. J. J. Org. Chem. 1993, 58, 2880.
580
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Table 1. Diastereoselectivity of imine 18 reduction
have found that the NaBH4/EtOH system (entry A) was
especially convenient for the lab scale preparations of amine
6. Upon the reaction quench, secondary amine 23 was
isolated from the mixture as a tosylate salt in 77% yield.
During this isolation the chiral purity of 23 was further
enhanced to >97% de as a result of the diastereomeric salt
rejection.
entry
reaction conditions
% de 23
A
B
C
D
E
F
NaBH4, EtOH, 0 °C, 2 h
NaBH4, MeOH, 0 °C, 2 h
Na(OAc)3BH, MeOH, 0 °C, 93 h
Na(OPiv)3BHi, MeOH, 0 °C, 93 h
Dibal-H, THF, 0 °C, 22 h
94
93
97
97
80
93
5% Pd/C (10 wt %), MeOH/toluene,
40 psi H2, ambient
At the same time, heterogeneous hydrogenation conditions
using Pd/C, Pd(OH)2/C, Pt/C, and PtO2 (entries F-L) were
most suitable for a pilot plant scale process. Although the
platinum catalyst gave slightly better reduction selectivity,
utilization of a palladium based catalyst in the process was
more desirable due to its lower cost and the possibility of
combining the reduction step and the debenzylation step into
a one-pot process (both steps could be conducted in the
presence of the same catalyst). Upon further optimization
we have found that the diastereoselectivity of the imine
reduction in the presence of a palladium catalyst could be
improved when the reaction was conducted at lower tem-
peratures (compare entries H and L, Table 1). The latter
conditions were selected for a kilogram scale process.
Chemoselective debenzylation of amine 23 was examined
next. We were pleased to find that both Pd/C and Pd(OH)2/C
catalysts gave highly selective auxiliary cleavage under
hydrogenation conditions yielding the desired amine 6.
Surprisingly though, we observed a substantial erosion of
the chiral purity of 6 upon reaction completion. Thus,
debenzylations of amine 23 with 97% de purity typically
gave amine 6 with only ∼80% ee purity. We suspected that
the deterioration of the amine chiral purity could occur via
its partial racemization through the imine intermediate,16 as
shown in eq 10.
G
H
I
5% Pt/C (10 wt %), MeOH/toluene,
40 psi H2, ambient
5% Pd(OH)2/C (20 wt %), MeOH/toluene,
40 psi H2, ambient
10% Pt/C (5 wt %), MeOH/toluene,
40 psi H2, 0-12 °C
PtO2 (10 mol %)/HOAc, MeOH/toluene,
40 psi H2, 0 °C
95
91
96
96
96
95
J
K
L
5% Pd/C (5 wt %), MeOH/toluene,
40 psi H2, 0-12 °C
5% Pd(OH)2/C (10 wt %), MeOH/toluene,
40 psi H2, 0-12 °C
subjected to a diastereoselective reduction with the formation
of a secondary amine intermediate 21, possessing a new
stereogenic center. The auxiliary is then debenzylated
affording chiral amine 22.14
However, in those cases where R1 or R2 of amine 21 is
an aryl substituent, the debenzylation reaction could proceed
in a nonselective fashion with the formation of a mixture of
desired amine and the deaminated side product.15
Although, the possibility of a nonselective debenzylation
also exists in the case of secondary amine intermediate 23
(our precursor to 6, eq 8), we were pleased to observe only
minor undesired cleavage of the C1-N bond under the
reaction conditions. The success of the debenzylation reaction
ultimately allowed us to apply the above methodology to
the large-scale synthesis of chiral amine 6 (eq 8).
Thus, refluxing a solution of 14 and (R)-(+)-R-methyl-
benzylamine in toluene resulted in the formation of imine
18. The equivalent of water produced in this reaction had to
be removed via a slow azeotropic distillation at ambient
pressure to achieve the desired (better than 90%) conversion
of the starting material. The whole process typically required
15 to 24 h and was accompanied by some imine degradation
as judged by HPLC analysis. Our attempts to further improve
the imine formation rate under acid catalysis conditions
demonstrated that trace amounts of acid (e.g., TFA) acceler-
ated the reaction; however, they also catalyzed the degrada-
tion of 18. On the other hand, the presence of excess (R)-
(+)-R-methylbenzylamine resulted in improved stability of
this imine. Under the optimized conditions the process was
carried in the presence of 2 equiv of the amine reagent, and
the resulting imine solution was then subjected to the
diastereoselective reduction without further purification.
Select results for the optimization of the diastereoselective
reduction of imine 18 are presented in Table 1. The desired
level of diastereoselectivity (>90% de) was achieved using
either borohydride reagents (entries A-D) or catalytic
hydrogenation conditions (entries F-L). In particular, we
To support this hypothesis a high purity sample of 6 was
subjected to the debenzylation conditions in the presence of
Pd(OH)2/C catalyst (eq 10). Indeed, after 24 h the recovered
6 showed significant loss of its enantiomeric purity, along
with formation of tert-butylindan (24, R ) tert-butyl) as a
side product (entry A in Table 2). Interestingly, when the
unsubstituted analogue of aminoindan 6 (R ) H) was
subjected to the same reaction conditions (entry B in Table
2), very little enantiomeric deterioration and deamination
were observed, indicating that these side reactions were
primarily induced by a tert-butyl substituent of 6. An optimal
control over the debenzylation of amine 23 was achieved
upon extensive optimization of the reaction parameters. It
was found that utilization of a less active catalyst (Pd/C vs
Pd(OH)2/C) and the interruption of the reaction at ∼96%
conversion of the starting material helped to maintain the
chiral purity of 6 at the better than 90% ee level (entry C,
Table 2).
(16) Murahashi, S.; Yoshimura, N.; Tsumiyama, T.; Kojima, T. J. Am. Chem.
Soc. 1983, 105, 5002.
(15) For example, see ref 14a, c, e, f.
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581

Table 2. 1-Aminoindans racemization in the presence of palladium catalysts
initial
% ee
final
% ee
deamination
(%)
entry
substrate
conditions
A
B
C
6, R ) tert-butyl
R ) H
99
99
5% Pd(OH)2, MeOH, HOAc, H2O,
40 psi H2, ambient, 24 h
5% Pd(OH)2, MeOH, HOAc, H2O,
40 psi H2, ambient, 24 h
5% Pd/C, MeOH, HOAc, 40 psi H2,
40 °C, 20 h
66
96
90
36
<10
12
6, R ) tert-butyl
>99
These debenzylation conditions were successfully dem-
onstrated in the kilogram scale process. The desired purity
of isolated 6 could be achieved upon its crystallization in
the form of a tosylate salt (6-TosH). Such isolation also
resulted in the enhancement of the enantiomeric purity of 6
to better than 95% ee (see Experimental Section for details).
For pilot plant scale preparations the synthesis of chiral
amine 6 from indanone 14 was further streamlined into a
one-pot process (eq 11).
the product directly precipitated from the reaction mixture
upon cooling and was typically isolated in 80% yield on a
kilogram scale.
The coupling of 25 with chiral aminoindan was achieved
in DMF at rt using diisopropylethylamine as a base (eq 13).17
The final deprotection step was accomplished by the reaction
of the penultimate intermediate 26 with methanolic sodium
hydroxide.
Thus, following imine 18 formation, the product solution
was concentrated under a vacuum, diluted with methanol,
and hydrogenated at 0-8 °C in the presence of a palladium
catalyst. Upon completion of the reduction, acetic acid was
added to the mixture and the hydrogenation was continued
over the same catalyst at 40 °C achieving the chemoselective
auxiliary cleavage. Using this highly practical method for a
kilogram scale preparation of chiral amine 6, the tosylate
salt 6-TosH was isolated in a 70% overall yield (for four
chemical steps starting from 14) with 100% chemical purity
and >97% ee chiral purity.
3. Final Coupling Strategy. Preparation of ABT-102.
With both building blocks (3 and 6) needed for ABT-102
preparation in hand, the final urea coupling process was
investigated. In small-scale experiments, the original dis-
covery method utilized phosgene for isocyanate 4 formation
from aminoindazole 3, followed by coupling with chiral
aminoindan 6 (Scheme 1) to give the desired product in high
yield. However, due to the low stability of the isocyanate
intermediate this process could only be efficiently conducted
in ether under high dilution conditions. For a kilogram scale
process the unstable isocyanate was replaced with shelf stable
succinimidyl carbamate derivative 25.17 Carbamate 25 was
conveniently prepared by reacting aminoindazole hydrochlo-
ride 3 with disuccinimidylcarbonate in the presence of
pyridine as a base (eq 12). Using acetonitrile as the solvent,
It was later found that both coupling and deprotection
steps could be conveniently incorporated into a one-pot
process. The product was precipitated from the reaction
mixture with addition of a methanol/water mixture. The crude
isolated 2 was then recrystallized from methanol or aqueous
ethanol in 90% yield to afford the API with desirable physical
properties. Chiral HPLC analysis of 2 showed the enantio-
meric purity of 2 to be >99% ee.
Conclusions
A highly efficient asymmetric synthesis of ABT-102 was
developed and successfully demonstrated on a multi-kilogram
scale. This process features a very practical asymmetric
synthesis of (R)-tert-butylaminoindan 6 as a key intermediate.
A high level of asymmetric induction was achieved through
the auxiliary induced stereoselective reduction of the cor-
responding iminoindan. Amine 6 was efficiently elaborated
into ABT-102 via coupling with a succinimidylcarbamate
derivative of the corresponding aminoindazole.
Experimental Section
Reaction mixtures and purities of the isolated products
were monitored by GC or HPLC method (Zorbax Rx C8
colum, detection at 205 nm).
(17) Takeda, K.; Akagi, Y.; Saiki, A.; Tsukahara, T.; Ogura, H. Tetrahedron
Lett. 1983, 24, 4569.
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4-Nitro-1H-indazole (10).4 A sodium nitrite (2.37 kg,
34.3 mol) solution in water (6.0 kg) is slowly added to a
preheated to 50 °C solution of 2-methyl-3-nitroaniline (2.5
kg, 16.4 mol) in acetic acid (53 kg) while maintaining the
internal temperature between 45 and 55 °C. The mixture is
stirred for an additional 1 h at 50 °C and then concentrated
under reduced pressure to an approximate volume of 10 L.
Water (30 kg) is charged to the reactor. The contents of the
reactor are distilled again to an approximate volume of 10
L. Water (30 kg) is charged to the reactor, and the resulting
orange slurry is cooled to 20 °C. The product was filtered,
washed with water (30 kg), and dried to 2.6 kg (95% yield).
If the above reaction was conducted at ambient temper-
ature, precipitation of triazene intermediate 12 was ob-
served: 1H NMR (DMSO-d6, δ, ppm): 2.45 (s, 6H), 7.40
(t, 2H), 7.61 (d, 2H), 7.81 (d, 2H).
solution is concentrated in vacuo. The residue is then diluted
with methylene chloride (0.5 kg) for direct use in the
cyclization step, as follows.
Chloroketone 16 solution is slowly added over a 1 h
period to concd sulfuric acid (59 kg) preheated to 90 °C.
After an additional 1 h at 90 °C the reaction mixture is
checked by an HPLC method for the reaction completion
and cooled to 15-20 °C. The reaction mixture is then
quenched by slow transfer into a mixture of water-MTBE-
heptanes (30:5.5:5.0 kg) while maintaining the internal
temperature below 10 °C. The organic layer is then separated
and washed with 5% aqueous potassium carbonate. The
organic layer is concentrated in vacuo, and the resulting oil
is assayed for ketone 14 (3.7 kg, 83% yield from tert-
butylbenzene) and is used directly in the imine formation
step.
1-Methoxycarbonyl-4-nitro-1H-indazole (13).2 A solu-
tion of nitroindazole 10 (2.4 kg, 14.7 mol) in DMF (17 kg)
is cooled to 5 °C. DBU (2.45 kg, 16.1 mol) is then charged
to the reactor while maintaining the internal temperature
below 15 °C. Methyl chloroformate (1.65 kg, 17.4 mol) is
then charged to the reactor over ∼1.5 h while maintaining
the internal temperature below 25 °C. The reaction mixture
is stirred for 30 min at 20 °C and quenched by the addition
of aqueous KH2PO4 (1 kg in 11 kg of water) while
maintaining the internal temperature below 25 °C. The brown
precipitate is filtered and washed with water (30 kg). The
wet cake is then charged back into the reactor and slurried
in isopropyl acetate (14 kg), and the mixture is then
concentrated in vacuo to an approximate volume of 10 L.
The mixture is diluted with isopropyl acetate (20 kg). The
product is filtered, washed with isopropyl acetate, and dried
to 2.8 kg of 13 (88% yield).
1-Methoxycarbonyl-4-amino-1H-indazole Hydrochlo-
ride (3).2 A slurry of nitroindazole 13 (2.8 kg, 11.0 mol) in
ethyl acetate (50 kg) is transferred into a hydrogenator
containing 5% Pd/C (0.24 kg) while maintaining a nitrogen
atmosphere. The reactor is then gassed with hydrogen, and
the mixture is stirred under 40 psi of hydrogen while
maintaining the internal temperature 40-45 °C. Upon the
reaction completion the catalyst is filtered off. The filtrate
is then treated with gaseous HCl (0.58 kg, 15.9 mol). The
precipitated salt is filtered, washed with ethyl acetate, and
dried under a vacuum to afford 3 (2.36 kg, 92% yield).
5-tert-Butylindan-1-one (14).6 3-Chloropropionyl chlo-
ride (3.2 kg, 25.2 mol) is added over 15-30 min to a slurry
of aluminum chloride (3.3 kg, 24.8 mol) in methylene
chloride (40 kg) at 0-5 °C under a nitrogen atmosphere.
Then tert-butylbenzene (32 kg, 23.9 mol) is charged to the
above mixture over ∼1 h maintaining the internal temper-
ature below 5 °C. The mixture is stirred at 0-5 °C for an
additional 0.5 h. The reaction mixture is quenched by
transferring into a reactor containing 10% aqueous hydro-
chloric acid (52 kg) while maintaining the internal temper-
ature below 10 °C. After the phase separation the organic
layer is diluted with heptanes. The resulting solution is then
concentrated via vacuum distillation to an ∼10 L volume,
and the residue is diluted with heptanes. The heptanes
Synthesis of (R)-(5-tert-Butylindan-1-yl)amine 6. (A)
Imine 18 Formation. To a solution of 14 (3.66 kg by assay,
19.5 mol) in toluene (26 kg) is added (R)-(+)-R-methylben-
zylamine (19, 4.8 kg, 40 mol). The solution is then heated
to reflux and slowly distilled under atmospheric pressure to
an approximately 12 L volume. If the conversion of 14 has
not reached 90%, more toluene is added, and the atmospheric
pressure distillation is continued until the conversion target
is achieved. The resulting solution of 18 is then cooled to rt
and used directly in the reduction step.
(B) Preparation of Chiral Aminoindan 6. The solution
of imine 18, prepared as described above in part A, is diluted
with methanol (30 kg) and transferred under a nitrogen
atmosphere into a hydrogenator charged with 5% Pd/C
catalyst (1.15 kg).
The mixture is cooled to 0 °C and hydrogenated at ∼40
psi pressure while maintaining the reaction temperature
below 10 °C. Upon the reaction completion the internal
temperature was adjusted to 20 ( 5 °C and acetic acid (2.92
kg) is added to the reaction mixture. The reaction mixture
is then further hydrogenated at 40 °C until ∼96% conversion
of amine 23 was achieved, as judged by an HPLC method.
The reaction mixture is cooled to rt, and the catalyst is
filtered off. Chiral analysis determined ∼82% ee purity of 6
at this point. The methanolic solution of 6 is then added to
a solution of tosic acid (3.4 kg, 17.8 mol) in methanol (5.1
kg). The resultant solution is distilled under reduced pressure
to an approximately 20 L volume. The internal temperature
is adjusted to ∼65 °C, and water (32 L) is added while
maintaining the internal temperature above 60 °C. The
product crystallizes out during the addition. The mixture is
held at ∼65 °C for 1 h and then slowly cooled to ∼20 °C.
After mixing at ∼20 °C the crude salt 6-TosH is collected
by filtration. The wetcake is washed with water (5 kg) and
purged with nitrogen. The crude salt 6-TosH is then charged
back to the reactor and diluted with toluene (21 kg) and
methanol (2.3 kg), and the mixture is heated to ∼65 °C and
then gradually cooled to ∼20 °C. The product is filtered,
washed with toluene, and dried under a vacuum to give
6-TosH (4.9 kg, 70% yield for three steps starting with 14,
97% ee chiral purity). 1H NMR (CD3OD, δ, ppm): 1.31 (s,
9H), 1.98-2.13 (m, 1 H), 2.36 (s, 3H), 2.48-2.63 (m, 1H),
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2.88-3.01 (m, 1H), 3.06-3.19 (m, 1H), 4.67-4.76 (m, 1H),
7.21 (d, 2H), 7.28-7.35 (m, 1H), 7.36-7.43 (m, 2H), 7.68
(d, 2H).
9.4 mol) is charged to the reactor while maintaining the
internal temperature below 25 °C. The reaction mixture is
then heated to 40 °C for not less than 5 h. Upon the reaction
completion, the mixture is cooled back to room temperature.
The precipitate is filtered, washed with acetonitrile, and dried
under a vacuum to give intermediate 25 (2.6 kg, 86% yield).
Synthesis of (R)-1-(5-tert-butylindan-1-yl)-3-(1H-inda-
zol-4-yl)urea (ABT-102, 2).3 Diisopropylethylamine (1.4 kg,
2.1 equiv) is added over 0.5 h to a slurry of active carbamate
25 (1.54 kg, 4.6 mol) and chiral aminoindan salt 6-TosH
(1.72 kg, 4.76 mol) in DMF (7.2 kg) while maintaining the
internal temperature below 20 °C. After an additional 30 min
a sodium hydroxide (0.45 kg, 11.2 mol) solution in methanol
(7.5 kg) is added to the mixture over 10-20 min while
maintaining the internal temperature below 20 °C. After an
additional 30 min at rt the mixture is diluted with methanol
(5.4 kg) and the product is precipitated via slow addition of
water (16.5 kg). The product is then filtered off and washed
with methanol-water (1:1). The crude 2 is dried under a
vacuum and redissolved in ethanol (3A, 200 proof, 20 kg)
at reflux. The solution is then distilled under an ∼200 mmHg
vacuum to an ∼16 L volume. The reaction mixture temper-
ature is adjusted to 40 ( 5 °C, and water (6.3 kg) is added
over 1 h to the resulting slurry. The mixture is cooled to rt,
and the product is filtered off, washed with ethanol-water
(70:30), and dried under a vacuum to give ABT-102 (2, 1.38
kg, 86% yield, >99% ee chiral purity).
Sodium Borohydride Reduction of Imine 18. Prepara-
tion of (R)-5-tert-Butyl-N-((R)-1-phenylethyl)-1-indanyl-
1-amine Tosylate (23-TosH). The solution of imine 18 (0.46
kg by assay, 1.58 mol), prepared as described above, is
slowly added to a slurry of sodium borohydride (0.137 kg,
3.16 mol) in ethanol (2.0 kg) while maintaining the reaction
temperature below 10 °C. The mixing is continued at 10 °C
until the reaction is complete (HPLC method). The reaction
mixture is then quenched by careful addition of 10% aqueous
KH2PO4 (4.1 kg) while maintaining the reaction temperature
below 10 °C.
The organic layer is separated and washed with 10%
aqueous KH2PO4 (2.0 kg). The organic layer is concentrated
in vacuo and diluted with ethyl acetate (0.7 kg). The resulting
amine solution is then added to a solution of tosic acid (0.35
kg, 1.83 mol) in ethyl acetate (2.6 kg.). The internal
temperature is adjusted to ∼65 °C and then slowly cooled
to ∼20 °C. After the solution mixed at 20 °C, the crude salt
23-TosH is collected by filtration. The wetcake is washed
with ethyl acetate (2 × 0.7 kg) and dried under a vacuum to
1
give 23-TosH (0.6 kg, 71% yield). H NMR (CD3OD, δ,
ppm): 1.31 (s, 9H), 1.69 (d, 3H), 2.10-2.26 (m, 1H), 2.36
(s, 3H), 2.37-2.51 (m, 1H), 2.83-2.97 (m, 1H), 3.06-3.24
(m, 1H), 4.50-4.62 (m, 1H), 4.62-4.69 (m, 1H), 7.21 (d,
2H), 7.30-7.37 (m, 1H), 7.37-7.52 (m, 5H), 7.52-7.61 (m,
2H), 7.69 (d, 2H).
Preparation of Methyl 4-[(2,5-Dioxopyrrolidine-1-
yloxy)carbonylamino]-1H-indazole-1-carboxylate (25). A
slurry of aminoindazole hydrochloride 3 (1.95 kg, 8.6 mol)
and N,N′-dissuccinimidylcarbonate (2.4, kg, 9.4 mol) in
acetonitrile (25 kg) is cooled to 10 °C. Pyridine (0.74 kg,
Acknowledgment
This paper is dedicated to Professor Yoshito Kishi on the
occassion of his 70th birthday.
Received for review November 2, 2006.
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