Process improvements for the preparation of kilo quantities of a series of isoindoline compounds

Article abstract of DOI:10.1021/op020225p

A series of isoindoline analogues with either an indazole (HMR 2934, HMR 2651) or benzisoxazole (HMR 2543) appendage were prepared for the proposed treatment of psychiatric disorders such as obsessive compulsive disorder and attention deficit disorder. The isoindoline compounds were prepared by reduction of the corresponding phthalimides with LiAlH₄. One compound was not chiral, and the other two required an enantioselective synthesis. The key step for these optically active analogues involved the coupling by an S_N2 process of either a piperazynyl intermediate or a piperdinyl intermediate with methyl 3-benzyloxy-2-trifluoromethansulfonatopropionate. The products for these two analogues had >98% ee. Process improvements led to the multi-kilogram syntheses of each of these compounds.

Full text of DOI:10.1021/op020225p

Organic Process Research & Development 2003, 7, 521−532
Process Improvements for the Preparation of Kilo Quantities of a Series of
Isoindoline Compounds
Timothy J. Watson,† Timothy A. Ayers,*,‡ Nik Shah,§ David Wenstrup,§ Mark Webster,| David Freund,§
Stephen Horgan,§ and James P. Carey
AVentis, Route 202-206, P.O. Box 6800, Bridgewater, New Jersey 08807, U.S.A.
Abstract:
A series of isoindoline analogues with either an indazole (HMR
2934, HMR 2651) or benzisoxazole (HMR 2543) appendage
were prepared for the proposed treatment of psychiatric
disorders such as obsessive compulsive disorder and attention
deficit disorder. The isoindoline compounds were prepared by
reduction of the corresponding phthalimides with LiAlH4. One
compound was not chiral, and the other two required an
enantioselective synthesis. The key step for these optically active
analogues involved the coupling by an SN2 process of either a
piperazynyl intermediate or a piperdinyl intermediate with
methyl 3-benzyloxy-2-trifluoromethansulfonatopropionate. The
products for these two analogues had >98% ee. Process
improvements led to the multi-kilogram syntheses of each of
these compounds.
Introduction
Drugs for the treatment of psychiatric disorders such as
obsessive compulsive disorder and attention deficit disorder
bromoacetonitrile. A small amount of the dialkylation product
are continuing targets of the pharmaceutical industry. Inda-
was also observed which was removed in the next step. The
zoles 1 and 2 and benzisoxazole 3 bearing an isoindoline
key to the isolation of piperazine 4 was treating the reaction
mixture with gaseous carbon dioxide to precipitate the excess
piperazine as the carboxylate salt. In total, over 10 kg of 4
was prepared for the synthesis of HMR 2934. The other
component required for the synthesis of 1 was prepared from
chlorofluorobenzoic acid 5 as shown. Thus, acid 5 was
converted into the corresponding tosyl hydrazone by reaction
with thionyl chloride followed by treatment with tosylhy-
drazine. Conversion to the intermediate chloroimidate 7 was
accomplished using thionyl chloride. Coupling of piperazine
4 and chloroimidate 7 was performed by addition of solid
chloroimidate 7 to a solution of piperazine 4. The order and
mode of addition was critical to obtain a high yield of
intermediate 8, as exposure of chloroimidates to catalytic
organic bases will promote conversion to tetrazene deriva-
tives such as 9.3,4 In addition, a tertiary amine such as Et3N
appendage1 were advanced as potential drug candidates, and
kilogram supplies of active pharmaceutical ingredient (API)
were required to support their development. Herein, we
describe process improvements in the syntheses of isoindo-
lines 1-3 leading to the preparation of kilo quantities of
each of these compounds.
HMR 2934
Compound 1 (HMR 2934) has the simplest structure of
the isoindolines that were prepared; however, some key
elements in the synthesis and handling of isoindolines as well
as the synthesis of the core indazole heterocycle were
established with this compound.2 The synthesis of 1 required
two pieces as shown in Scheme 1. Piperazine 4 was prepared
in a straightforward manner by alkylation of piperazine with
* To whom correspondence should be addressed. E-mail: timothy.ayers@
aventis.com.
(2) For a description of earlier work done on the indazole synthesis, see: (a)
Hendrix, J. A.; Shimshock, S. J.; Shutske, G. M.; Tomer, J. D., IV; Kapples,
K. J.; Palermo, M. G.; Corbett, T. J.; Vargas, H. M.; Kafka, S.; Brooks, K.
M.; Laws-Ricker, L.; Lee, D. K. H.; de Lannoy, I.; Bordeleau, M.; Rizkalla,
G.; Owolabi, J.; Kamboj, R. K. ChemBioChem 2002, 3, 999. (b) Leroy, V.;
Lee, G. E.; Lin, J.; Herman, S. H.; Lee, T. B. Org. Process Res. DeV. 2001,
5, 179. (c) Strupczewski, J. T.; Bordeau, K. J. U.S. Patent 4,954,503, 1990.
(3) Tetrazene 9 becomes the major product if the mode of addition is reversed.
The amount of tetrazene 9 formed was not typically quantified, as it readily
precipitates during sample preparation for analyses.
† Present address: Pfizer Inc., Chemical Research and Development, Eastern
Point Road, Groton, CT 06340-8013.
‡ Process Development, Bridgewater, NJ.
§ Chemical Development, Cincinnati, OH.
| Present address: Procter & Gamble, 8700 Mason-Montgomery Road, Mason,
OH 45040.
Present address: Merck & Co., 466 Devon Park Drive, Wayne, PA 19087.
(1) For a recent review of isoxazole chemistry, see: Bonnett, R.; North, S. A.
The Chemistry of Isoindoles. In AdVances in Heterocyclic Chemistry;
Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1981;
Vol 29, p 341.
(4) Catalytic Et3N has been described to promote tetrazene formation; see:
Shawali, A. S.; Fahmi, A.-G. A. J. Heterocycl. Chem. 1977, 14, 1089.
10.1021/op020225p CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/06/2003
Vol. 7, No. 4, 2003 / Organic Process Research & Development
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521

Scheme 1
Scheme 2
The completion of the HMR 2934 (1) campaign required
conversion of the nitrile functionality of 10 into the isoin-
doline moiety (Scheme 3). This transformation was ac-
complished by first reduction of nitrile 10 to the correspond-
ing primary amine using hydrogen and Raney-Ni as the
catalyst. The presence of ammonia is essential, as the catalyst
does not turnover under the conditions employed without
ammonia present, presumably because of catalyst complex-
ation to the product amine. In addition, this process was much
easier operationally than the LiAlH4 method previously used
in the discovery route, where isolation of the primary amine
from the aluminum salts was problematic.2 The amine was
not isolated but rather was converted directly to phthalimide
16 by reaction with fluorophthalic anhydride. Conversion
to the phthalimide was very exothermic and required careful
temperature control to ensure generation of the intermediate
amide acid. The reaction was subsequently heated to 50 °C
to promote dehydration to the desired phthalimide 16.
The most problematic step of the synthesis involved
reduction of the phthalimide functionality to the desired
isoindoline 1, owing to the relatively facile oxidation of the
isoindoline to the corresponding isoindole 17.1,5 Indeed, the
reduction of the phthalimide moiety was initially ac-
complished using Red-Al at 85 °C (the reaction proceeds
much slower at lower temperatures) to provide isoindole 17
as the major product and not the isoindoline. This mixture
was treated with NaB(OAc)3H to reduce 17 to 1. This process
although tedious provided a reasonable yield of the desired
isoindoline 1. We decided to explore other conditions for
the direct transformation of the phthalimide to the isoindoline
or DABCO has been employed to scavenge the HCl during
the reaction; however, to maximize yields and the ease of
the preparation of piperazine 4, a second equivalent of 4 was
used in this case. Intermediate 8 was not isolated but was
subjected directly to the cyclization conditions to provide
indazole 10. The use of powdered instead of granular K2CO3
was essential in order to obtain good rates for indazole
formation.
Other Aspects of Indazole Formation. During the course
of this drug development program, we also prepared 6-meth-
oxy-substituted indazole derivatives. Thus, bromoacid 11 was
converted to chloroimidate 12 as shown in Scheme 2. The
chloroimidate was treated with a variety of amines to
generate the intermediate 13. Interestingly, when one tries
to thermally cyclize (up to 160 °C) intermediate 13, a much
more electron-rich derivative compared to 8, in the presence
of powdered K2CO3, less than 2% of indazole formation was
observed. However, the use of catalytic CuI (2.6 mol %)
promotes cyclization so that excellent yields are obtained
for the series of indazoles 14a-e. In addition, refluxing
i-PrOH can be used as the solvent under these conditions.
This process was used to prepare 100-g quantities of the
unprotected piperarzinyl derivative 15 after removal of the
ethyl carbamate and benzenesulfonate groups from 14a. In
the campaign for the preparation of HMR 2934, the use of
catalytic CuI lowered the required reaction temperature to
70-80 °C from 120 °C for the cyclization of 8 to indazole
10, but this added little advantage and was not used.
(5) For leading references for the oxidation of isoindolines to isoindoles, see:
Kreher, R. P.; Herd, K. J. Chem. Ber., 1988, 121, 1827. Kreher, R.; Kohl,
N.; Use, G. Angew. Chem.; GE 1982, 94, 634-635.
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Scheme 3
Table 1. Reduction of Phthalimide 16 to Isoindoline 1
Scheme 4
scale
entry (g)
temp isoindoline 1: des-fluoro products
reducing agent (°C) isoindole 17
18 (%), 19 (%)
1
2
3
4
5
6
7
8
103 Red-Al
10 Red-Al
Red-Al
36 LiAlH4/THF
650 LiAlH4/THF
85
85
85
70
70
<10:>90
<10:>90
<10:>90
70:30
70:30
60:40
3.3, 6.1
0.67, 3.3
0.08, 1.3
0.08, 1.2
0.3, 1.3
0.55, 0.88
0.38, 0.70
0.18, 0.68
4
2
4
1
LiAlH4‚2THF/tol 45
LiAlH4‚2THF/tol 25
93:7
LiAlH4‚2THF/tol 0-5 >93:<7
(see Table 1). Quite nicely, the use of LiAlH4‚2THF complex
in toluene provided high conversion to the desired isoindoline
1 with minimal formation of isoindole 17, even at 0 °C.6
However, control of the reaction temperature was essential
to minimize isoindole 17 and des-fluoro products 18 and 19.
Even though small amounts of isoindole 17 could be removed
in subsequent steps, the des-fluoro products were inseparable
from the final product. An additional aspect of using the
LiAlH4‚2THF complex in toluene was the relative ease of
the workup with water to provide easy removal of the
aluminum salts by filtration. After the LiAlH4 reduction, the
free base of the isoindoline was converted to the dihydro-
chloride salt for purification by digesting the solid in
methanol. Finally, the dichloride salt was converted to the
monohydrochloride salt as the final drug substance. A total
of 3.7 kg of HMR 2934 (1) was prepared using this
chemistry.
substituent, so it is less prone to oxidation compared to HMR
2934. A disadvantage is that HMR 2651 has a chiral center
in the molecule, and the optical purity of the drug substance
and intermediates need to be monitored to ensure the desired
optical purity in the final product.
The synthesis of 2 required an unfunctionalized piperazine
20. Previous studies used a monoprotected piperazine deriva-
tive for the construction of the desired piperazine intermedi-
ate. Subsequent deprotection of the piperazine was thus
required. The use of simple piperazine in this process would
avoid the deprotection step and would also retain the tosyl
group on the indazole nitrogen; the unprotected indazole
causes some complications at a later stage in the synthesis
(vide infra). Attempts to prepare the unsubstituted piperazinyl
derivative directly were explored by treating chloroimidate
7 with excess piperazine (Scheme 4). After much experi-
mentation, we found that the best conditions for the genera-
tion of intermediate 21 involved the use of a 10-fold excess
of piperazine with MeOH containing a small amount of
AcOH as solvent, principally because of problems associated
with the solubility of piperazine. However, when the cy-
clization was performed with or without Cu-catalysis, a
substantial amount of byproducts were formed and the overall
yield of indazole 20 was about 20-30% for the two steps.
HMR 2651
After the preparation of HMR 2934, the back-up com-
pound HMR 2651 (2) was advanced as the leading candidate.
This compound possesses the indazole heterocycle as well
as the isoindoline moiety. A synthetic advantage for HMR
2651 was that the isoindoline does not have the fluoro
(6) The use of the soluble LAH•2THF species in scale-up is our preferred
reducing agent. It is easy to handle, and issues with slurries are avoided. In
addition, the workup to remove the aluminum salts is easily accomplished.
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523

Scheme 5
concentration of methyl ester 27 to ensure no epimerization
of the center occurred.
With the two pieces in hand, coupling via the triflate was
readily accomplished (Scheme 7). Thus, treatment of a
solution of alcohol 27 in toluene at 0 °C by slow addition
of triflic anhydride to control the exothermic reaction
provided a toluene solution of triflate 28. This solution was
directly added to a solution of piperazine 23 to provide the
coupled product 29. Complete inversion of the triflate center
was observerd, as no signicant loss of optical purity was
observed. Reduction of ester 29 with LiAlH4‚2THF gave
primary alcohol 30. These steps proceeded smoothly on a
kilo scale. The next sequence of events required the
conversion of primary alcohol 30 to the isoindoline moiety.
In this case, we decided to use a Gabriel approach for the
conversion of alcohol 30 to phthalimide 31 by transformation
of the alcohol to an appropriate leaving group for displace-
ment with potassium phthalimide. Initially, a Mitsunobu
reaction was used for this reaction, but the production of
the side products (triphenylphosphine oxide and dihydro-
DEAD) in this reaction made it very unattractive for scale-
up. We then focused on the preparation of the mesylate.
Unfortunately, the use of mesyl chloride resulted in sub-
stantial formation of the chloro adduct that was less reactive
to displacement with potassium phthalimide. We found that
mesyl anhydride provided smooth transformation of the
alcohol to the mesylate at low temperatures, and now addition
of the potassium phthalimide provided 31. A complication
that was unknown during the scale-up of this process was
the generation of regioisomer 32 in the reaction. Isomer 32
presumably is formed via aziridinium intermediate 33 by
competitive addition of the phthalimide to either the primary
or secondary site of the aziridinium moiety.7 This impurity
was not an issue, as it was removed in subsequent steps of
the process. Another complication in the mesylate forming
step that also hampered detection of regioisomer 32 is that
the indazole nitrogen is mesylated to some extent (10-20%.)
This phenomenon required the use of 1.5 equiv of mesyl
anhydride to obtain complete conversion of alcohol 30 to
the intermediate mesylate. However, the mesyl group on the
indazole is removed upon reduction with LiAlH4‚2THF to
isoindoline 34. The reduction process developed for HMR
2934 (1) worked even more efficiently in this case, because
unsubstituted isoindoline 34 was less prone to oxidation to
the corresponding isoindole. Isoindoline 34 was not isolated
but was treated directly with boron tribromide to remove
the benzyl group to provide 2 as the dihydrobromide salt.
Conversion of the dihydrobromide salt to the ditosylate salt
was subsequently done to provide the desired salt form of
the API. This process was used to prepare over 4 kg of HMR
2651 (2).
Scheme 6
Because the reaction with simple piperazine seemed
untenable, we decided to prepare piperazinyl indazole 22
using ethylcarbamylpiperazine (Scheme 5). Once again, the
order of addition is critical to minimize the formation of the
tetrazene. Instead of using a tertiary amine such as Et3N or
DABCO to scavenge the HCl during the reaction, a second
equivalent of inexpensive ethylcarbamylpiperazine was used
to increase the yield of the process. The tosyl and carbamate
groups were removed in the next stage by treatment with
HCl at 105 °C to provide indazole 23.
The chiral portion of the molecule was prepared from an
L-serine derivative (Scheme 6). Boc-protected compound 24
was used as the starting material, because it is available in
kilogram quantities. Initially, the boc-group was removed
with HCl, and amino acid 25 was isolated to ensure removal
of residual chloride which generated impurities in the
diazotization step. Subsequently, we found that removal of
the boc-group of 24 with H2SO4 eliminated the need for
isolation and this solution could be directly treated with
sodium nitrite for the diazotization chemistry to give hydroxy
acid 26. Subsequently, hydroxy acid 26 was converted to
methyl ester 27 using standard conditions. No loss of optical
purity was observed in this sequence as >98% ee of methyl
ester 27 was obtained. However, care had to be taken in the
HMR 2543
Following the preparation of HMR 2651 (2), back-up
compound HMR 2543 (3) was selected for further develop-
(7) The extent of aziridinium formation in this process will be discussed in a
subsequent publication describing an alternative synthesis involving an
aziridinium approach for the preparation of compounds 2 and 3.
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Scheme 7
Scheme 8
ment. This compound is structurally similar to both prede-
cessor compounds in that it has the fluoro-substituted
isoindoline moiety (HMR 2934) and the chiral appendage
(HMR 2651.) However, the indazole functionality with a
piperazine appendage has been changed to a benzisoxazole
group8 with a piperidine moiety. The strategy was similar
for the construction of HMR 2543 compared to HMR 2651,
involving the coupling of piperidine 35 with triflate 28.
Piperidine 35 had been previously prepared in-house on a
multikilogram scale (Scheme 8.)9
With both pieces in hand, coupling of piperidine 35 with
triflate 28 occurred smoothly to provide ester 36 (Scheme
9). Ester 36 was reduced with LiAlH4‚2THF to give alcohol
37. Now the phthalimide moiety could be incorporated into
the molecule as before. However, in the case of HMR 2543
(3), the preparation of potassium fluorophthalimide 38 was
required and readily achieved by treatment of fluorophthalic
anhydride with formamide and subsequent formation of the
potassium salt with KOH (Scheme 10). Similar to case of
HMR 2651, during the mesylate formation and displacement
reaction, a mixture of phthalimide regioisomers 39 and 40
was obtained, presumably via an aziridinium intermediate.5
However, in this case, phthalimide 39 was isolated as the
hydrochloride salt and the undesired isomer remained in the
filtrate. Reduction of phthalimide 39 with LiAlH4‚2THF
proceeded smoothly to provide isoindoline 41. Note that, in
the case of the benzisoxazole 39, there is no complication
of a mesylated nitrogen as was the case for the synthesis of
HMR 2543. Compound 41 was not isolated but reacted with
boron tribromide to remove the benzyl group to give 3 as
the dihydrobromide salt. Subsequent transformation to the
dimaleate salt provided the desired drug substance. This
process was used to prepare 3.5 kg of HMR 2543 (3).
(8) For a recent review of isoxazole chemistry, see: Guartieri, F.; Gianella, M.
1,2-Benzisoxazoles. In The Chemistry of Heterocycles; Grunanger, P., Vita-
Finzi, P., Eds.; Isoxazoles, Vol. 49 Part 2; John Wiley & Sons: New York,
1999; Chapter 1.
(9) Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.; Stache,
U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F. P.; Dunn, R.
W. J. Med. Chem. 1985, 28, 761. Strupczewski, J. T.; Gardner, B. A.; Allen,
R. C. U.S. Patent 4,355,037, 1982.
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525

Scheme 9
Scheme 10
in a reaction flask, stirred, and CO2 (g) was bubbled into
the mixture to form the carbonate salt of the unreacted
piperazine (the temperature changed from 20 °C to 42 °C).
The CO2 (g) addition was stopped once the temperature
started to drop. The carbonate salt was filtered off, and the
filtrate evaporated to a residue at 45 °C/50 Torr to give 1.07
kg of N-cyanomethylpiperazine (99% yield) as an oil that
was 87% pure (GC). GC method: Hewlett-Packard 5890
GC with a 3392A integrator; injector temperature ) 250 °C;
detector temperature ) 270 °C; oven temperature ) 100 °C
for 2 min and then 100-250 °C at 20 °C/min. The capillary
column used was an HP-1 methyl silicone gum (10 m ×
0.53 mm × 2.65 µm film thickness).
Summary
In summary, we have described the multikilogram syn-
thesis of a series of isoindolines from the simple compound
HMR 2934 to the more complex molecules HMR 2651 and
HMR 2543. The improvements identified during these
campaigns facilitated the rapid scale-up and ensured that the
availability of drug substance remained off the critical path
for drug development.
{[Chloro(2-chloro-4-fluorophenyl)methylene]hydrzide}-
4-methylbenzenesulfonic Acid (7). A mixture of 2.8 kg
(16.0 mol) of 2-chloro-4-fluorobenzoic acid, toluene (34 L),
and 1-methyl-2-pyrrolidinone [NMP] (200 mL) was stirred
and heated under nitrogen at 78 °C. Thionyl chloride (1.3
L, 17.8 mol) was added to the reaction mixture over a 2-h
period while the temperature was maintained at 78 °C. The
mixture was stirred for 2 h at 85 °C and then cooled to 60
°C, and 3.8 kg (20.4 mol) of p-toluenesulfonylhydrazide was
added portionwise over 10 min while a temperature of 60
°C was maintained. The mixture was heated at 100 °C for 3
h and cooled to 25 °C, and heptane (30 L) was added. The
resulting solid was filtered off, washed with heptane (10 L),
and air-dried. The solid was returned to the reaction vessel
under nitrogen, and thionyl chloride (11 L) was added over
15 min at 25 °C. The mixture was slowly heated to and
maintained at 78 °C for 3.5 h until gas evolution stopped.
The mixture was cooled to 25 °C, heptane (40 L) was added,
Experimental Section
General. NMR spectra were recorded on a Varian XL
300 and/or Varian GEMINI-300 spectrometers at 300 MHz
for 1H and 75 MHz for 13C. Reactions were conducted under
a nitrogen atmosphere unless otherwise noted. Spectral and
elemental analyses were performed by the Analytical and
Structural Sciences Department, Cincinnati.
4-Cyanomethylpiperazine (4). Piperazine (2.0 kg, 23.2
mole) was dissolved in 10 L of acetonitrile at 50 °C.
Chloroacetonitrile (642 g) was dissolved in 4 L of acetoni-
trile, and the solution was then added over 3.5 h to the
reaction mixture in order to keep the formation of dicyano-
methyl piperazine to a minimum. The reaction was monitored
by GC as stated in the following. The reaction mixture was
stirred for an additional 30 min, cooled to ambient temper-
ature, and the solid was filtered off. The filtrate was placed
526
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and the resulting slurry was stirred at 10 °C for an additional
18 h. The solid was filtered and washed with heptane (10
L) to give 6.1 kg of crude 7. The solid was recrystallized
from ethyl acetate (5L), toluene (25 L), and heptane (40 L)
at 80 °C. The resulting mixture was stirred for 18 h while
cooling to 10 °C, and then the solid was collected by
filtration, washed with heptane (20 L), and air-dried to give
5.70 kg of 7 (98%, 99.6% HPLC purity, tR 7 ) 5.2 min).
HPLC Method A: Nucleosil C18 250 × 4 mm2 (5 micron);
wavelength ) 240 nm; 1 mL/min; 55% ACN/45% H2O with
0.05 N ammonium dihydrogen phosphate. 1H NMR (CDCl3)
δ 8.32 (s, 1), 7.91-7.81 (m, 2), 7.44-6.94 (m, 4), 2.42 (s,
3), 1.62 (s, 1).
6-Fluoro-3-[1-(4-cyanomethylpiperazinyl)]-1-(4-meth-
ylphenyl)sulfonyl-1H-indazole (10). A mixture of N-cy-
anomethylpiperazine (2.9 kg, 23 mol, 80-90% pure) and
THF (32 L) was stirred at 25 °C while 7 (3.5 kg, 9.7 mol)
was added portionwise over 2 h as a solid while an internal
temperature of 21-29 °C was maintained. After 30 min at
25 °C, the THF was removed at 35 °C (50 Torr.) The residue
was dissolved in NMP (14 L), and 5.5 kg of finely milled
K2CO3 was added. The stirred mixture was heated at 126
°C for 1 h, and the reaction progress was followed by HPLC
[(Method A) tR 10 ) 13.0 min]. The mixture was cooled to
40 °C, and methanol (14 L) was added. Water (56 L) was
slowly added over a 45-min period at 25 °C, and the resulting
precipitate was slurried for an additional 18 h. The solid was
collected by filtration, washed with 60 L of water, and then
dried at 70 °C/50 Torr for 18 h to give 2.9 kg (73%, 98.9%
HPLC purity) of 10: 1H NMR (CDCl3) δ 7.96-6.95 (m,
7), 3.58 (s, 2), 3.48 (m, 4), 2.71 (m, 4), 2.37 (s, 3).
6-Fluoro-3-[4-[2-(5-fluoro-1,3-dihydro-1,3-dioxo-2H-
isoindol-2-yl)ethyl]-1-piperazinyl]-1-[(4-methylphenyl)sul-
fonyl]-1H-indazole (16). A mixture of 10 (1.32 kg, 3.2 mol),
Raney Ni (Davidson lot no. 8149, 840 g “wet”), and 2 N
NH3 in ethanol (12 L) was placed under 200 psi of hydrogen
and heated at 80 °C. After 4 h, the hydrogen uptake ceased.
The mixture was cooled and filtered through a bed of Celite,
which was washed with ethanol (8 L). The filtrate was
concentrated at 35 °C/50 Torr. The residue was dissolved
in CH2Cl2 (20 L) and dried over 1 kg of MgSO4. The drying
agent was filtered off, washed with CH2Cl2 (2 L), and the
filtrate was concentrated at 30 °C/50 Torr. (Hydrogenations
were run on a 1.3-kg scale and were combined for the
following step.) The foamy residues from four hydrogenation
runs (5.1 kg) were dissolved in THF (16 L) and cooled to
15 °C. To this mixture was added 4-fluorophthalic anhydride
(2.23 kg, 1.1 eq, 14 mol) dissolved in THF (7.5 L) at a rate
so that the reaction temperature did not exceed 20 °C. The
mixture was heated at 70 °C for 18 h, and the reaction was
monitored by HPLC Method B: Nucleosil C18 250 × 4 mm2
(5 micron); wavelength ) 240 nm; 1 mL/min; 70% ACN/
30% H2O with 0.05 N ammonium dihydrogen phosphate;
tR 10 ) 5.3 min; tR 16 ) 8.9 min. THF was removed via
distillation at 40 °C/50 Torr. Ethanol (14 L) was added and
the remaining THF was removed until the distillation
temperature remained at 78 °C. Another portion of ethanol
(8 L) was added, and the mixture was heated at 78 °C for
18 h. The mixture was cooled to 5 °C, and the solid was
collected by filtration and washed with ethanol (10 L). The
solid was dried at 60 °C/50 Torr to give 5.4 kg (75%, 97.8%
1
HPLC purity) of 16: H NMR (d6-DMSO) δ 7.98-7.12 (m,
10), 3.71 (m, 2), 3.28 (m, 6), 2.58 (m, 4), 2.22 (s, 3).
6-Fluoro-3-[4-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-
yl)ethyl]-1-piperazinyl]-monohydochloride-1H-indazole
[HMR 2934 Monohydrochloride (1)]. To a slurry of 95%
LiAlH4 (1.1 kg, 26.9 mol, 4 eq) in toluene (22.5 L) cooled
to 5-15 °C was slowly added THF (4.36 L, 53.7 mol, 2
equiv to LiAlH4) to form a 1 M LiAlH4‚2THF complex in
toluene solution. This mixture was warmed to 35 °C for 30
min and then stirred at 20 °C for 18 h. (1 M LiAlH4‚2THF
solutions in toluene are commercially available.)
The LiAlH4 solution was cooled to 0 °C, and 16 (3.8 kg,
6.7 mol) was added in 500 g portions over a 1.5-h period
while the mixture maintained an internal temperature of <8
°C. The temperature of the reaction mixture was raised to
20 °C, and the reaction progress was monitored by HPLC
Method B: tR compound 16 ) 8.9 min; tR isoindoline 1 )
3.0 min; tR isoindole 18 ) 4.5 min. After 4.5 h, the mixture
was cooled to 0 °C and slowly hydrolyzed with water (2.4
L). (Caution: water addition must stay below 15-20 °C or
oxidation will proceed; THF (16L) was added during this
process due to the thick nature of the aluminum salts and
insolubility of the free base in toluene.) The mixture was
filtered through a Nutsche filter and washed with 3 × 8 L
of THF. The filtrate was washed with saturated sodium
bicarbonate (10 L) and brine (10 L). The organic solution
was dried over 1.5 kg of MgSO4. The drying agent was
filtered off and washed with THF (8 L), and the solvent was
removed at 20 °C/50 Torr to give 2.4 kg of HMR 2934 as
the free base as a 93:7 mixture of isoindoline 1 and isoindole
18 based upon HPLC analysis.
The free base was dissolved in 16 L of methanol
containing 0.1 M 2,6-di-tert-butyl-4-methylphenol (BHT),
and to this was added, in one portion, 1 N HCl in diethyl
ether (12.5 L, 2 equiv), followed by 12 L of diethyl ether.
The mixture was stirred at 15 °C for 18 h, and the solid was
collected by filtration and washed with tert-butyl methyl ether
(TBME) (10 L) to give 2.45 kg of HMR 2934 (1) as the
dihydrochloride salt. This solid and a 1.98-kg sample
prepared in a similar fashion were combined and digested
in 40 L of methanol at 60 °C for 30 min, cooled to 15 °C,
filtered, and dried at 85 °C/30 Torr to give 3.51 kg (57%,
95.4% HPLC purity) of HMR 2934 as the dihydrochloride
[HPLC Method C: Waters Symmetry C18 (5 micron);
wavelength ) 240 nm; 1 mL/min; 20% ACN/80% water
(0.05 N sodium phosphate); 20 min linear gradient to 40:
60. tR of 1 ) 12.1 min].
A. Further Purifications. Two batches were combined
(4.9 kg) and digested 3 times in 55 L of methanol at 60 °C
for 30 min (following the same procedure previously
mentioned for filtration.) A total of 3.96 kg (80% for these
purifications. 98.6% HPLC purity, Method C) of HMR 2934
(1) as the dihydrochloride salt was obtained. (OVerall
reduction and purification yield was 47%.)
Vol. 7, No. 4, 2003 / Organic Process Research & Development
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527

Precooled ethyl acetate (30 L)/THF (30 L) and 1 N KOH
(40 L) were combined at 10 °C, and to this stirred mixture
was added HMR 2934 dihydrochloride (3.9 kg, 8.5 mol).
The mixture was stirred for 30 min at 10 °C. The phases
were separated, and the aqueous phase was extracted with 2
L of a 1:1 ethyl acetate/THF. The combined organic extracts
were washed twice with saturated sodium bicarbonate (40
L each) and dried over Na2SO4 (5 kg). The drying agent
was filtered off and washed with ethyl acetate (10 L)
followed by diethyl ether (8 L), and the solvent was removed
at <20 °C/50 Torr to give 3.19 kg of the free base of HMR
2934 (1). The free base was dissolved in THF (50 L), and
to this was added 1 M HCl in Et2O (7.49 L, 0.90 equiv)
over a 20-min period at 19 °C. The mixture was stirred for
30 min and filtered through a Nutsche filter (6 h for
filtration). The solid was washed with THF (2 L), followed
by two slurries with 32 and 24 L of diethyl ether. The solid
was dried at 85 °C/30 Torr for 5 h and then slowly cooled
to 25 °C under 30 Torr for 15 h to give 3.20 kg (89%, 98.5%
HPLC purity, Method C) of HMR 2934 (1) as the mono-
hydrochloride salt: Karl Fischer (0.5% H2O); Cl- titration
(theory 8.44%; found 8.40%). 1H NMR (d6-DMSO) δ 12.18
(s, 1), 7.81 (m, 1), 7.38-6.76 (m, 5), 4.24 (m, 4), 4.01 (m,
6), 3.28 (m, 2), 3.02 (m, 4). Anal. Calcd for C21H24ClF2N5:
C 60.06; H, 5.76; N, 16.67. Found: C; 59.77; H, 5.98; N,
16.83.
Step 3: A mixture of 58.0 g (0.24 mol) of 2-bromo-5-
methoxybenzoylhydrazide and 350 mL of pyridine was
charged to a 1-L three-necked flask fitted with a magnetic
stirrer, thermometer, cooling bath, and continuous nitrogen
purge. The stirred solution was cooled to and maintained at
-10 °C while 31.3 mL (0.25 mol) of benzenesulfonyl
chloride was added via syringe over 25 min. Stirring was
continued at -10 °C for 30 min, and then the cooling bath
was removed and the reaction mixture was stirred at ambient
temperature for 2 h. The reaction mixture was poured into a
mixture of 580 mL of ethyl acetate and 1.6 L of water. After
the mixture was stirred for 5 min, the organic phase was
separated and washed with a solution of 580 mL H2O/120
mL saturated NaCl. The organic phase was separated and
evaporated to a viscous residue at 70 °C/50 Torr, and then
the residue was diluted with 500 mL of H2O. The viscous
residue solidified readily. Solid was filtered off, washed with
3 × 100 mL of H2O, and then air-dried to give 90 g of crude
product (odor of pyridine). Crude product was dissolved in
540 mL of boiling 2-propanol. The sample was gravity
filtered to remove trace insolubles, and then the filtrate stood
at ambient temperature for 8 h. The solid which crystallized
was filtered off, washed with 2 × 100 mL of 2-propanol,
and then dried at 45 °C/50 Torr for 16 h to give 78.4 g (86%)
of 2-bromo-5-methoxybenzoic acid 2-phenylsulfonyl hy-
1
drazide: mp 149-150 °C; H NMR (DMSO-d6) δ 10.56
(bs, 1H, D2O exchangeable), 10.24 (bs, 1H, D2O exchange-
able), 7.96-7.81 (m, 2), 7.72-7.48 (m, 4), 6.98 (dd, 1, J )
4, 8 Hz), 6.74 (d, 1, J ) 4 Hz), 3.78 (s, 3). Elemental analysis
calculated for C14H13BrN2O4S: C, 43.65; H, 3.40; N, 7.27.
Found: C, 43.75, 43.67; H, 3.44, 3.34; N, 7.25, 7.26.
Step 4: A mixture of 500 g (1.30 mol) of 2-bromo-5-
methoxybenzoic acid 2-phenylsulfonylhydrazide and 1.25 L
of thionyl chloride was charged to a 5-L three-necked flask
fitted with a stirrer, heating mantle, and condenser. The
stirred mixture was heated at gentle reflux, and the off gases
were passed into 5 L of H2O. Off-gassing ended about 2 h
after reaching reflux. A total of 625 mL of SOCl2 was
distilled from the reaction mixture at atmospheric pressure.
The residue was vigorously stirred while 2.5 L of hexane
were slowly added. After the mixture was stirred for 30 min,
the white solid which precipitated was filtered off, washed
with hexane, and then air-dried at ambient temperature to
give 495 g (94%) of 12: mp 105-107 °C; 1H NMR (CDCl3)
δ 8.32 (s, 1), 8.02-7.97 (m, 2), 7.67-7.51 (m, 3), 7.42 (d,
1, J ) 8 Hz), 6.88-6.80 (m, 2), 3.78 (s, 3).
Ethyl 1-{[(Phenylsulfonyl)hydrazono](2-bromo-5-meth-
oxyphenyl)methyl}-4-piperazinecarboxylate (13a). To a
solution of 158 g (1.0 mol) of ethyl 1-piperazinecarboxylate
in 600 mL of THF cooled below 5 °C was added 200 g
(0.50 mol) of chloride 12 dropwise over 2 h while the
reaction temperature was maintained below 5 °C. The
solution was allowed to warm to room temperature. After 6
h, 600 mL of water and 100 mL of a 10% aqueous KHSO4
solution were added. (NOTE: KHSO4 is necessary to
dissolve the excess piperazinecarbamate.) EtOAc (1 L) was
added and the organic phase was washed with brine. The
combined aqueous phases were extracted with 400 mL of
Methoxy Indazoles. r-Chloro-2-bromo-5-methoxyben-
zaldehyde-2-phenylsulfonylhydrazone (12). Step 1: A
mixture of 2.99 kg (12.9 mol) of 2-bromo-5-methoxybenzoic
acid, 192 mL (3.6 mol) of H2SO4 and 6.0 L of EtOH was
charged to a 22-L three-necked flask fitted with a stirrer,
condenser, and heating mantle. The stirred mixture was
heated at reflux for 20 h. Heating was discontinued, and 600
g (4.34 mol) of potassium carbonate was carefully added
(foaming) portionwise. Solvent was removed at 40 °C/50
Torr. The residue obtained was extracted with 2 × 6 L of
CH2Cl2. Organic extracts were combined, dried (MgSO4),
and filtered to remove drying agent which was washed with
CH2Cl2. The filtrate was concentrated at 25 °C/50 Torr to
1
give 3.17 kg of ethyl 2-bromo-5-methoxybenzoate: H NMR
(CDCl3) δ 7.50 (d, 1, J ) 9 Hz), 7.29 (d, 1, J ) 3.1 Hz),
6.87 (dd, 1, J ) 3 Hz, 9 Hz), 4.40 (q, 2H, J ) 7 Hz), 3.81
(s, 3), 1.41 (t, 3, J ) 7 Hz).
Step 2: A solution of 2.45 L (50.5 mol) of hydrazine
monohydrate and 6.0 L of absolute EtOH was charged to a
22-L three-necked flask fitted with a stirrer, condenser,
thermometer, and dropping funnel. The stirred solution was
heated to 78 °C, and then 3.17 kg (12.2 mol) of ethyl
2-bromo-5-methoxybenzoate was added over 1.5 h. The
stirred mixture was heated at reflux for 7 h and then stirred
while cooling to room temperature overnight. Product which
crystallized was filtered off, washed with absolute EtOH,
and then air-dried at ambient temperature to give 2.33 kg
(78%) of 2-bromo-5-methoxybenzoylhydrazide: mp 172-
173 °C; 1H NMR (DMSO-d6) δ 9.50 (bs, 1H, exchangeable
with D2O), 7.51 (d, 1, J ) 9 Hz), 6.90-6.97 (m, 2), 4.44 (d,
2, J ) 4 Hz, exchangeable with D2O), 3.76 (s, 3).
528
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development

EtOAc. The combined organic phases were dried (MgSO4)
and concentrated. The crude oil was dissolved in 500 mL of
hot EtOAc, and 500 mL of heptane was added. After the
mixture was allowed to stand for 3 d, complete crystallization
had occurred. The solid was collected and air-dried for 3
days to give 246 g (94%) of 13a: mp 102-106 °C; 1H NMR
δ 9.78 (br s, 1), 7.93-7.56 (m, 5), 7.49 (d, 1, J ) 9 Hz),
6.92 (dd, 1, J ) 3, 9 Hz), 6.40 (d, 1, J ) 3 Hz), 4.05 (q, 2,
J ) 7 Hz), 3.65 (s, 3), 3.47 (m, 4), 3.09 (m, 4), 1.18 (t, 3,
J ) 7 Hz).
cooled to 65 °C, and 30 L of EtOH was added. The solution
was divided into two equal portions, and 60 L of H2O was
added to each half with good agitation. The product
crystallized and was collected by filtration. The combined
solids were washed with 60 L of H2O and air-dried to give
6.06 kg (84%, 95% HPLC purity) of 22: 1H NMR (d6-
DMSO) δ 8.20-7.41 (m, 7), 4.24 (q, 2, J ) 7 Hz), 3.68
(m, 4), 3.58 (m, 4), 2.43 (s, 3), 1.38 (t, 3, J ) 7 Hz). Anal.
Calcd For C21H23FN4O4S: C, 56.49; H, 5.19; N, 12.55.
Found: C, 56.24; H, 5.34; N, 12.30.
3-(4-Ethylcarbamyl-1-piperazinyl)-5-methoxy-1-phe-
nylsulfonyl-1H-indazole (14a). A mixture of 100 g (0.19
mol) of 13a, 32 g (0.23 mol) of powdered K2CO3, and 1.0
g (0.005 mol) of CuI in 0.5 L of 2-propanol was heated to
reflux for 5.5 h. An aliquot was removed and concentrated.
1H NMR showed complete conversion. The mixture was
cooled to ∼60 °C, and 1 L of water was added. After 30
min, the mixture was cooled with an ice bath. The solid was
collected, washed with water, and allowed to air-dry for 3
days to give 84 g (99%) of 14a: mp 140-141 °C; 1H NMR
δ 8.00-7.20 (m, 8), 4.08 (q, 2, J ) 7 Hz), 3.81 (s, 3), 3.50
(m, 4), 3.38 (m, 4), 1.21 (t, 3, J ) 7 Hz). Anal. Calcd. for
C21H24N4O5S: C, 56.74; H, 5.44; N, 12.60. Found: C, 57.10;
H, 5.23; N, 12.54.
6-Fluoro-3-(1-piperazinyl)-1H-indazole (23). A mixture
of 22 (6.0 kg, 13.3 mol) in H2O (10 L) and ethylene glycol
(12.5 L) was stirred while HCl was added (37%, 32.5 L).
The mixture was heated to 105 °C and maintained at this
temperature for 20 h. The reaction was monitored by HPLC
Method D: tR 22 ) 8.8 min, tR 23 ) 2.0 min. The reaction
mixture was cooled to 40 °C and gravity filtered to remove
insoluble material. The filtrate was concentrated at 60 °C/
50 Torr, and the residue was chased with three portions of
i-PrOH (6 L) to remove residual water. The residue was
slurried in i-PrOH (12 L) and cooled at 5 °C overnight. The
solid was filtered off, washed twice with 6 L portions of 5
°C i-PrOH, and air-dried to give 4.1 kg of 23 as the
hydrochloride salt.
5-Methoxy-3-(1-piperazinyl)-1H-indazole (15). To a
solution of 200 g (3.0 mol) of KOH in 600 mL of EtOH
and 600 mL of water was added 120 g (0.27 mol) of 14a.
The mixture was heated to reflux. After 18 h, the solution
was cooled to room temperature. The pH was adjusted to
<2 by the addition of 6 N HCl (∼800 mL). This solution
was extracted with EtOAc (3 × 0.5 L), discarding the organic
phase. The pH of the aqueous phase was adjusted to >9 by
the addition of a 10% NaOH solution. This solution was
extracted with CHCl3 (3 × 0.5 L.) The combined organic
phases were dried (MgSO4) and concentrated. Toluene (500
mL) was added to the residue to induce crystallization. The
solid was collected and dried in a vacuum oven at 60 °C for
8 h to give 31.8 g (51%) of 15: mp 173-175 °C; 1H NMR
δ 11.81, (s, 1), 7.24 (d, 1, J ) 9 Hz), 7.02 (d, 1, J ) 2 Hz),
6.93 (dd, 1, J ) 2, 9 Hz), 3.79 (s, 3), 3.19 (m, 4), 2.86 (m,
4). Anal. Calcd. for C12H16N4O: C, 62.05; H, 6.94; N, 24.12.
Found: C, 61.89; H, 6.97; N, 24.15.
6-Fluoro-3-[1-(4-ethoxycarbonyl)piperazinyl]-1-(4-me-
thylphenyl)sulfonyl-1H-indazole (22). A solution of ethyl
1-piperazinecarboxylate (6.0 kg, 41.4 mol) in THF (60 L)
was stirred at 20 °C, and 7 (6.0 kg, 16.6 mol) was added in
small portions over a period of 2.5 h. After 0.5 h at 20 °C,
the reaction mixture was stripped to a residue at 40 °C/50
Torr. This residue was dissolved in NMP (30 L), and finely
ground potassium carbonate (9.0 kg) was added. The mixture
was heated to 125 °C (a small exotherm occurred between
110 and 120 °C) and held at this temperature for 1 h. The
reaction was monitored by HPLC Method D: Waters
Symmetry C18, 3.9 × 150 mm2; wavelength ) 214 nm; flow
1 mL/min; solvent A, 25% ACN/75% buffer; solvent B, 45%
ACN/55% buffer; buffer, 0.05 M NaH2PO4, pH ) 3.0;
gradient 100% A to 100% B over 30 min (HPLC tR of 7 )
5.0 min, tR of 22 ) 8.8 min). The reaction mixture was
The hydrochloride salt was dissolved in 40 L of H2O,
and KHCO3 (3.0 kg, 30.0 mol) was added in small portions
(final pH ) 8.0). The precipitated solid was collected by
filtration, washed 3 times with H2O (6 L), and air-dried to
give 2.42 kg of 23 as the monohydrate. After the solid was
dried in a vacuum oven at 80 °C/50 Torr for 20 h, 2.25 kg
(77%, 97.5% HPLC purity, Method D) of 23 as the
monohydrate was produced: H NMR (d6-DMSO) δ 12.01
(s, 1), 7.78 (m, 1), 7.08 (m, 1), 6.80 (m, 1), 3.21 (m, 4),
2.84 (m, 4).
1
(S)-3-Benzyloxy-2-hydroxypropanoic Acid (26). A mix-
ture of boc-O-benzyl-L-serine 24 (2.00 kg, 6.77 mol) in 2 N
H2SO4 (8 L) was stirred and heated at 75 °C for 1 h. TLC:
EtOAc, Rf boc-O-benzyl-L-serine 24 ) 0.7, Rf deprotected
amino acid 25 ) 0.0. The resulting solution was cooled to
0 °C, and a solution of NaNO2 (835 g, 12.1 mol) in H2O (8
L) was added over 2 h while the temperature was maintained
between 0 and 5 °C. After complete addition, the reaction
mixture was stirred at this temperature for 10 h followed by
stirring at ambient temperature for 2 h. The reaction mixture
was adjusted to pH ) 4 with 1.25 L of 50% NaOH. EtOAc
(12 L) was added, and the layers were vigorously stirred
while the aqueous layer was adjusted to a pH of 2 with 0.2
L of H2SO4. [There is an unidentified white solid that forms
between the organic and aqueous layer before the pH
adjustment with H2SO4. This solid dissipates when the pH
reaches 2 and the organic layer visually becomes dark
orange.] The aqueous layer was extracted further with EtOAc
(2 × 12 L). The combined extracts were dried over Na2-
SO4. The drying agent was filtered off and washed with
EtOAc (4 L), and the filtrate was concentrated at 40 °C/50
1
Torr to give 1.26 kg (93%) of 26: H NMR (CDCl3) δ 7.38-
7.28 (m, 5), 4.59 (m, 2), 4.38 (m, 1), 3.78 (m, 2).
Vol. 7, No. 4, 2003 / Organic Process Research & Development
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529

Methyl (S)-3-Benzyloxy-2-hydroxypropionate (27). A
mixture of 26 (3.94 kg, 20.1 mol), MeOH (27 L), and freshly
prepared methanolic HCl (1 M, 8.2 L) was stirred at ambient
temperature for 1.5 h. Trimethyl orthoformate (4.39 L) was
added, and the mixture was stirred at ambient temperature
for 18 h. The solution was concentrated at 20 °C/30 Torr,
and the resulting oil was dissolved in 50 L of methyl tert-
butyl ether (MTBE). Decolorizing charcoal (500 g) and
MgSO4 (500 g) were added to the stirred solution and then
filtered through filter aid (the high dilution was used to
remove the small amounts of benzyloxy-L-serine present).
The solution was then concentrated at 20 °C/30 Torr to give
3.59 kg (85%, 98.4% ee chiral HPLC purity, Method E) of
27. The ee was determined by HPLC Method E: Chiralcel
OD, 4:1 heptane/ethanol with 0.5% HNEt2, isocratic, 1 mL/
min, wavelength ) 254. tR of methyl (S)-3-benzyloxy-2-
hydroxypropionate (27) ) 8.7 min; tR of enantiomer ) 9.8
A solution of methanesulfonic anhydride (4.40 kg, 20.1 mol)
in acetonitrile (10 L) was added over 3 h while the
temperature was maintained between -18 and -20 °C. The
formation of the mesylate was complete by TLC: silica gel;
EtOAc; Rf 30 ) 0.25, Rf mesylate intermediate ) 0.75.
Potassium phthalimide (6.97 kg, 37.6 mol) was added in one
portion at -20 °C, and the reaction mixture was slowly
warmed to 20 °C over 1.5 h and then stirred overnight at
ambient temperature. The reaction was monitored by HPLC
Method D: tR 30 ) 9.4 min, tR 31 ) 25.2 min. The insoluble
material was filtered off, and the filter cake was washed with
12 L of acetonitrile. The filtrate was stripped to a residue at
30 °C/30 Torr. The residue was dissolved in toluene (12 L)
and this solution was filtered to remove some precipitated
material. The toluene solution was used in the next step.
(3-Benzyloxy-(2S-{4-[6-fluoro-1H-indazol-3-yl]piper-
azin}-1-yl)-propyl)-isoindole (34). A 1 M solution of
LiAlH4‚2THF complex in toluene (44.1 kg. 50.4 mol) was
cooled to 0 °C and the solution of 31 in toluene from above
was added over 1.5 h while the reaction temperature was
maintained between 0 and 5 °C. The mixture was warmed
to 20 °C and stirred at this temperature for 2 h. The reaction
was monitored by HPLC Method D: tR 31 ) 25.4 min; tR
34 ) 24.1 min. The reaction was cooled to 0 °C, and H2O
(3.63 L) was slowly added, followed by THF (12 L), and
finally an additional 3.63 L of H2O. The reaction mixture
was stirred overnight at ambient temperature, and then 10
kg of Na2SO4 was added. After 1 h, the aluminum salts were
removed by filtration through filter aid, and the filter cake
was washed with THF (28 L). The combined filtrates were
stripped to a residue at 25 °C/30 Torr to give 4.45 kg (74%)
of 34.
(3-Hydroxy-(2S-{4-[6-fluoro-1H-indazol-3-yl]piperazin}-
1-yl)-propyl)-isoindole Di-4-methylbenzenesulfonate [HMR
2651 (2)]. To a solution of 34 (4.05 kg, 8.34 mol) in CH2-
Cl2 (45 L) cooled to 0 °C was added a solution of boron
tribromide (4.00 kg, 16.0 mol) in CH2Cl2 (16 L) over 1 h
while the temperature was kept below 10 °C. (Caution:
SCBA equipment and full body protective clothing should
be used when working with this solution. One should take
every effort to avoid contact and inhalation.) The solution
was warmed to 15 °C and stirred at this temperature for 3 h.
The reaction was monitored by HPLC Method D: tR 34 )
24.1 min; tR HMR 2651 (2) ) 3.0 min. The reaction mixture
was cooled to 5 °C, and MeOH (15 L) was added in a slow
stream over 1 h while the temperature was kept below 10
°C. The reaction mixture was concentrated at 25 °C/30 Torr
to a final volume of about 8 L and slowly added to 92 L of
THF. The product was filtered off using a Nutsche filter,
washed with THF (12 L), and dried on the filter under
nitrogen to give 4.46 kg (96%) of HMR 2651 (2) as the
dihydrobromide salt.
1
min. H NMR (CDCl3) δ 7.39-7.26 (m, 5), 4.58 (m, 2),
4.35 (m, 1), 3.79 (s, 3), 3.77 (s, 2), 3.20 (br s, 1).
Methyl 3-Benzyloxy-2S-{4-[6-fluoro-1-(4-methylphen-
yl)sulfonyl-1H-indazol-3-yl]piperazin-1-yl)-propionate (29).
Triflate 28 formation: To a solution of 27 (2.39 kg, 11.4
mol) in toluene (19 L) cooled to 0 °C was added N,N-
diisopropylethylamine (DIPEA) (1.98 L, 11.4 mol). The
mixture was stirred while triflic anhydride (3.20 kg, 11.4
mol) was added over a 1.5-h period and the temperature was
maintained at <5 °C. The reaction was warmed to 20 °C.
After 1 h, the reaction was complete by TLC (silica gel;
ethyl acetate/heptane 50:50; Rf 28 ) 0.65; Rf 27 ) 0.45; Rf
29 ) 0.15). Coupling: To a mixture of 23 (2.50 kg, 11.4
mol) and DIPEA (1.98 L, 11.4 mol) in toluene (30 L) was
added the previously mentioned triflate solution over a period
of 10 min. The reaction was stirred at 20 °C overnight at
which time the reaction was complete by HPLC Method D:
tR 23 ) 1.3 min; tR 29 ) 20.8 min. The insoluble material
was removed by filtration through filter aid and washed with
toluene (6 L). The filtrate was concentrated at 20 °C/30 Torr
to a final volume of about 16 L and carried on the next step.
3-Benzyloxy-2S-[4-(6-fluoro-1H-indazol-3-yl)piperazin-
1-yl]-propan-1-ol (30). A 1 M solution of LiAlH4‚2THF
complex in toluene (19.9 kg. 22.7 mol) was cooled to 0 °C,
and the solution of 29 in toluene from the previously
mentioned was added over 2 h while the reaction temperature
was maintained between 0 and 5 °C. The mixture was
warmed to 20 °C. After 1 h, the reaction was complete by
HPLC Method D: tR 29 ) 20.8 min; tR 30 ) 9.4 min. The
reaction mixture was cooled to 0 °C, and H2O (1.65 L) was
slowly added, followed by THF (16 L), and finally an
additional 1.65 L of H2O. After the mixture was stirred
overnight at ambient temperature, 4 kg of Na2SO4 was added.
After 1 h, the aluminum salts were removed by filtration
through filter aid, and the filter cake was washed with THF
(10 L). The filtrate was concentrated to a residue at 30 °C/
50 Torr to give 4.03 kg of alcohol 30 as an amber oil.
2-(3-Benzyloxy-2S-{4-[6-fluoro-1H-indazol-3-yl]piper-
azin}-1-yl)propyl-isoindole-1,3-dione (31). Alcohol 30
(4.84 kg, 12.6 mol) was dissolved in acetonitrile (36 L) and
cooled to -20 °C, and DIPEA (4.60 L, 26.4 mol) was added.
A mixture of CH2Cl2 (46 L), MeOH (8 L), and H2O (32
L) was stirred, and HMR 2651 × 2HBr (4.49 kg, 8.06 mol)
was added in small portions over a period of 30 min. The
mixture was stirred, and 10% NaOH (6.5 L) was added over
a period of 1 h to bring the pH to 10.0. The organic layer
was separated, the aqueous layer extracted once with CH2-
530
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Vol. 7, No. 4, 2003 / Organic Process Research & Development

Cl2 (10 L), the combined organic extracts dried over 5 kg of
Na2SO4, and the solvent removed at 25 °C/50 Torr to give
2.66 kg (6.73 mol) of free base. The free base was dissolved
in THF (5 L) and added to a solution of p-toluenesulfonic
acid monohydrate (2.56 kg, 13.46 mol) in i-PrOH (13 L) at
55 °C. The solution was diluted with THF (16 L), seeded,
cooled to a final temperature of 5 °C, and kept at this
temperature for 1 h. The solid was collected by filtration,
washed with THF (16 L), and dried in a vacuum oven at
ambient temperature to give 2.09 kg (35%) of HMR 2651
(2) ditosylate.
concentrated at 20 °C/30 Torr to give 6.6 kg (>100%) of
36.
2-(3-Benzyloxy-2S-[4 fluorobenzo[d]isoxazol-3-yl]pip-
eridin-1-yl)-propan-1-ol (37). A 1 M solution of LiAlH4‚
2THF complex in toluene (40 L) was cooled to -2 °C, and
a solution of 36 (6.6 kg) in toluene (8 L) was added over
2.5 h while the reaction temperature was kept between 0
and 5 °C. The mixture was warmed to 15 °C. After 2 h, the
reaction was complete as shown by HPLC Method F: tR
36 ) 26.1 min; tR 37 ) 25.1 min. The reaction was cooled
to 0 °C, and H2O (2.8 L) was slowly added, followed by
THF (20 L), and finally additional H2O (2.8 L). The reaction
mixture was stirred overnight at ambient temperature, and
then 5 kg of Na2SO4 was added. After 1 h, the aluminum
salts were removed by filtration through filter aid, and the
filter cake washed with THF (20 L). The filtrate was
concentrated to a residue at 30 °C/50 Torr to give 6.4 kg
(93.5%) of 37 as an amber oil.
Potassium 4-Fluorophthalimide (38). Step 1: 4-Fluo-
rophthalic anhydride (1.25 kg, 7.53 mol) and 3.75 L of
formamide was charged to a 12-L flask. The stirred mixture
was heated to and held at 120 °C for 150 min while the
reaction was monitored by GC/MS [column HP-5 (30 m ×
0.25 mm × 0.25 µm film); injector temperature 250 °C;
temperature program was 50 °C for 1 min and then was
heated to 300 °C at the rate of 20 °C/min; tR 4-fluorophthalic
anhydride ) 6.7 min; tR 4-fluorophthalimide ) 8.1 min].
Upon completion, the reaction mixture was cooled to 115
°C and poured into 30 L of water. The resulting slurry was
stirred for 1.5 h, and the solids were collected by filtration
and washed with 3 × 1.5 L of water. The product was air-
dried to give 1.01 kg (81%) of 4-fluorophthalimide: mp
178-179 °C. Anal. Calcd: C, 58.19; H, 2.44; N, 8.48.
Found: C, 58.14; H, 2.59; N, 8.51.
Step 2: 4-Fluorophthalimide (967 g, 5.86 mol) and ethanol
(15 L) were charged to a 22 L flask. The mixture was heated
to 60 °C to achieve complete solution. A solution of 377 g
of KOH (377 g, 7.92 mol) in water (406 mL) was added
over 25 min. The resulting slurry was cooled and held at
<10 °C for 1 h. Solids were collected by filtration and
washed with 2 × 1 L of ethanol and then were dried at 40
°C/50 Torr to give 1.16 kg (98%) of 38: Anal. Calcd: C,
47.28; H, 1.49; N, 6.89. Found: C, 47.16; H, 1.51; N, 6.84.
2-{3-Benzyloxy-2-(S)-[4-(6-fluorobenzo[d]isoxazol-3-
yl)piperidin-1-yl]propyl}-5-fluoro-isoindole-1,3-dione Hy-
drochloride (39). To a solution of 37 (4.6 kg, 11.9 mol) in
acetonitrile (36 L) cooled to 0 °C was added DIPEA (2.91
kg, 22.5 mol). Methanesulfonic anhydride (3.13 kg, 14.3 mol)
dissolved in acetonitrile (5 L) was added over 70 min while
the temperature was maintained between 0 and 3 °C. The
formation of the mesylate was complete by TLC: silica gel;
EtOAc; Rf 37 ) 0.25; Rf of mesylate intermediate ) 0.75.
Potassium fluorophthalimide (2.0 kg, 9.8 mol) was added
in one portion at 0 °C, and the reaction mixture was slowly
warmed to 20 °C over 18 h. The reaction was complete as
shown by HPLC Method F: tR mesylate intermediate ) 25.1
min; tR 39 ) 29.4 min. The reaction was concentrated to a
residue at 30 °C/30 Torr and then partitioned between EtOAc
HMR 2651 ditosylate (4.288 kg) and 2,6-di-tert-butyl-4-
methylphenol (87 g) were dissolved in MeOH (104 L) at 65
°C (it was necessary to add 200 mL of H2O to obtain a
complete solution). The MeOH was removed by atmospheric
distillation gradually replacing by the addition of i-PrOH (86
L) until a final volume of about 100 L was obtained. The
solution was seeded with 256 g of HMR 2651 ditosylate
and cooled over a 5 h-period to a final temperature of -20
°C and held at this temperature for 18 h. The solid was
collected by filtration under nitrogen using a Nutchse filter,
washed with i-PrOH (5 × 15 L) and dried in a vacuum oven
at 25 °C/50 Torr for 18 h. The material was placed through
a #10 sieve then dried an additional 8 h at 60 °C/50 Torr to
give 3.73 kg (82%, 98.9% HPLC purity, Method D) of HMR
2651 (2) ditosylate. Overall, a 28% yield of 2 ditosylate was
1
obtained from 34: H NMR (d6-DMSO) δ 12.22 (s, 2), 10.69
(br s, 1), 9.84 (br s, 1), 7.83 (m, 1), 7.46-6.80 (m, 14), 5.05-
3.15 (m, 17), 2.28 (s, 6) Karl Fischer ) 0.24%. Anal. Calcd.
for C22H26FN5O x 2 C7H8O3S with 0.24% H2O: C, 58.30;
H, 5.57; N, 9.45. Found: C, 58.06; H, 5.57; N, 9.45.
Methyl 2-(3-Benzyloxy-2S-[4-fluorobenzo[d]isoxazol-
3-yl]piperidin-1-yl)-propionate (36). Triflate 28 forma-
tion: A solution of 27 (3.75 kg, 17.8 mol) in toluene (35 L)
was cooled to 0 °C, and DIPEA (2.28 kg, 17.7 mol) was
added. Triflic anhydride (5.0 kg, 17.8 mol) was added over
1.5 h while the reaction temperature was maintained at <5
°C. The reaction was warmed to 15 °C. After 2 h, the reaction
was complete by TLC (silica gel; ethyl acetate/heptane 50:
50; tR 28 ) 0.65; tR 27 ) 0.45. A second portion of DIEA
was added (2.28 kg, 17.7 mol). Coupling: Compound 35 as
the hydrochloride salt was treated with 5 L of NaOH and
50 L of CH2Cl2. The organic layers were separated, dried
over 1.0 kg of MgSO4, filtered (wash with 10 L CH2Cl2),
and concentrated to give 3.24 kg (14.7 mol) of 35 as the
free base. The free base was dissolved in toluene (24 L),
and this solution was cooled to 5 °C. The triflate solution
from the previously mentioned was added over a period of
10 min. The reaction mixture was stirred at 17 °C overnight.
The reaction was monitored by HPLC Method F: Waters
Symmetry C18, 3.9 × 150 mm2; wavelength ) 240 nm; flow
1 mL/min; solvent A ) ACN; solvent B ) 0.1% TFA in
water, 10:90 A/B 0-5 min, 5-25 min linear gradient to 50:
50 and hold for 5 min, 30-35 min linear gradient to 100:0
and hold for 5 min (tR 35 ) 14.4 min; tR 36 ) 26.1 min).
The insoluble material was removed by filtration through
filter aid and washed with toluene (10 L). The filtrate was
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531

(50 L) and water (25 L). The EtOAc layer was washed with
10 L of brine, dried over MgSO4 (2.0 kg), filtered, and
concentrated to give 7.2 kg of 39 as the free base. This
residue was dissolved in EtOAc (18 L), and 600 g of HCl
in 6 kg of TBME was added. After 30 min, the resulting
solid was collected by filtration and dried at 30 °C/50 Torr
to give 4.05 kg (73%) of 39 as the hydrochloride salt.
2-{3-Benzyloxy-2-(S)-[4-(6-fluorobenzo[d]isoxazol-3-
yl)piperidin-1-yl]propyl}-5-fluoro-isoindole (41). Phthal-
imide 39 as the hydrochloride salt (6.0 kg) was treated with
CH2Cl2 (80 L) and saturated sodium bicarbonate (37 L). The
organic phase was dried (MgSO4) and concentrated to a
residue. Compound 39 as the free base was dissolved into
toluene (15 L). A 1.0 M solution of LiAlH4‚2THF complex
in toluene (48 L) was cooled to -5 °C, and the toluene
solution of 39 was added over 100 min while the reaction
temperature was maintained between -5 and 5 °C. The
mixture was warmed to 20 °C. After 1 h, the reaction was
complete as shown by HPLC Method F: tR 39 ) 29.4 min;
tR 41 ) 27.6 min. The reaction was cooled to -5 °C, and
H2O (3.6 L) was slowly added, followed by THF (24 L),
and finally additional H2O (3.6 L). After the mixture was
stirred overnight at ambient temperature, Na2SO4 (6 kg) was
added. After 1 h, the aluminum salts were removed by
filtration through filter aid, and the filter cake was washed
with THF (26 L). The combined filtrates were concentrated
to a residue at 25 °C/30 Torr to give 5.6 kg (100%) of 41.
3-(2,3-Dihydro-5-fluoro-1H-isoindol-2-yl)-2-(S)-[4-(6-
fluoro-benzo[d]isoxazol-3-yl)piperidin-1yl]-propan-1-ol Di-
maleate [HMR 2543 (3)]. A solution of 41 (5.6 kg, 11.1
mol) in CH2Cl2 (50 L) was cooled to -2 °C. To the mixture
was added a solution of boron tribromide (7.6 kg, 30.4 mol)
in CH2Cl2 (20 L) over 75 min while the temperature was
kept below 5 °C. (Caution: SCBA equipment and full body
protective clothing should be used when working with this
solution. One should take every effort to avoid contact and
inhalation.) The reaction was monitored by HPLC Method
F: tR 41 ) 27.6 min; tR 3 ) 20.7 min. The reaction mixture
was cooled to 5 °C, and MeOH (45 L) was added in a slow
stream over a period of 3.5 h while the temperature was kept
below 10 °C. The reaction mixture was concentrated at 25
°C/30 Torr. The resulting residue was stirred in THF (24 L)
while 70 L TBME was added. The solid was collected by
filtration using a Nutsche filter, washed with TBME (20 L),
and dried on the filter under nitrogen to give 5.8 kg of HMR
2543 (3) as the dihydrobromide salt.
(10 L). The combined organic extracts were dried over
MgSO4 (2 kg). The solvent was removed at 25 °C/50 Torr
to give 4.3 kg of 3 as the free base. HMR 2543 (3) as the
free base was dissolved in MeOH (80 L) and added to a
solution of p-toluenesulfonic acid monohydrate (3.95 kg) in
i-PrOH (13 L) at 55 °C. The methanol was removed by
distillation, and 60 L of IPA was back added during the
process to maintain a constant volume (the pot temperature
remained at 74 °C). The solution was cooled to 0 °C and
held at this temperature for 18 h. The resulting solids were
collected by filtration, washed with IPA (10 L), and dried
in a vacuum oven at ambient temperature to give 5.5 kg of
HMR 2543 (3) as the ditosylate salt. The material was
combined with a 3.7-kg batch and recrystallized using the
previously mentioned procedure to give 5.8 kg (46%) of
HMR 2543 (3) as the ditosylate salt.
HMR 2543 (3) ditosylate (5.8 kg) was treated with CH2Cl2
(60 L) and 1 M NaOH (40 L). The organic phase was dried
(Na2SO4) and concentrated to give 2.98 kg of 3 as the free
base. This free base was dissolved in 100 L of IPA. To this
solution was added maleic acid (2.51 kg, 26.1 mol) and 150
g of BHT. The mixture was heated to 80 °C for 3 h and
then slowly cooled to 22 °C over 4 h. The resulting solids
were collected by filtration and washed with IPA (40 L)
1
followed by THF (50 L) and TBME (50 L). H NMR and
HPLC analysis (Method F) showed the presence of p-TsOH,
so the entire procedure was repeated. The final product was
dried at 25 °C/30 Torr for 18 h, 40 °C/30 Torr for 18 h, 60
°C/30 Torr for 18 h, and finally 80 °C/30 Torr for 18 h to
give 3.37 kg (67%) of HMR 2543 (3) as the dimaleate salt:
1H NMR (d6-DMSO) δ 8.03 (m, 1), 7.86 (m, 1), 7.60-7.07
(m, 4), 6.18 (s, 4), 4.24 (m, 4), 3.77-3.02 (m, 11), 2.08 (m,
4). Anal. Calcd for C23H25F2N3O2‚2 C4H4O4: C, 57.67; H,
5.15; N, 6.51. Found: C, 57.67; H, 5.05; N, 6.38.
Acknowledgment
The authors would like to thank Rick Nevill for his
intellectual contributions. The authors would also like to
acknowledge contributions made by Franz Weiberth, Tom
Lee, George Wong, Vincent Leroy, George Lee, and Zhongli
Gao for earlier work that was performed at the Hoescht
Roussel Pharmaceutical Research Institute.
Supporting Information Available
1H NMR spectra of most compounds are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
The salt was partitioned between CH2Cl2 (60 L) and
saturated sodium bicarbonate in H2O (40 L). The mixture
was stirred, and 50% NaOH (300 mL) was added over a
period of 1 h to bring the pH to 10.0. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
Received for review November 20, 2002.
OP020225P
532
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