Process development for ABT-472, a benzimidazole PARP inhibitor

Article abstract of DOI:10.1021/op7000194

A nine-step convergent process was developed for the synthesis of ABT-472, a benzimidazole PARP inhibitor. The identity and origin of several impurities were determined, and the process was modified to reduce or eliminate these impurities. A number of safety and control issues were investigated. The original synthesis was shortened to 9 steps and streamlined while maintaining a convergent strategy. A stable salt was selected, and control of the API solid form was established. The process was successfully scaled up to provide 8.5 kg of final product of >99% purity in 33% yield over 9 steps.

Full text of DOI:10.1021/op7000194

Organic Process Research & Development 2007, 11, 693−698
Process Development for ABT-472, a Benzimidazole PARP Inhibitor
Jufang H. Barkalow, Jeffrey Breting, Bruce J. Gaede,* Anthony R. Haight, Rodger Henry, Brian Kotecki, Jianzhang Mei,
Kurt B. Pearl, Jason S. Tedrow,† and Shekhar K. Viswanath
Process Chemistry and Engineering, Dept. R450, Bldg. R-8, Abbott Laboratories, 1401 Sheridan Road,
North Chicago, Illinois 60064, U.S.A.
Abstract:
°C, well above the boiling point of isopropyl acetate (85-
91 °C). The maximum rate of heat evolution ((dT/dt)max) was
reduced from 74 °C/min prior to dilution with isopropyl
acetate to less than 1 °C/min after dilution. The latter
experiment was run in the presence of stainless steel.
Slow addition of the anhydride 2 to an excess of
ammonium hydroxide yielded a 90:8:2 mixture of am-
monium salts of carboxamide 12,6 regioisomer 13,7,8 and
phthalic acid 1 (Scheme 2).9,10 Adjusting the pH of the
reaction mixture to not more than 2 with aqueous hydro-
chloric acid caused free acid 14 to precipitate in 80% yield
along with approximately 4% of the phthalic acid 1.
However, acid 14 was found to rapidly undergo isomerization
and hydrolysis to diacid 1 upon standing in acidic media
even at 0 °C.
A nine-step convergent process was developed for the synthesis
of ABT-472, a benzimidazole PARP inhibitor. The identity and
origin of several impurities were determined, and the process
was modified to reduce or eliminate these impurities. A number
of safety and control issues were investigated. The original
synthesis was shortened to 9 steps and streamlined while
maintaining a convergent strategy. A stable salt was selected,
and control of the API solid form was established. The process
was successfully scaled up to provide 8.5 kg of final product of
>99% purity in 33% yield over 9 steps.
Introduction
Poly((ADP)-ribose) polymerases (PARPs) have been
recognized as cellular signaling enzymes capable of cata-
lyzing the transfer of ADP-ribose units from NAD+ to a
number of acceptor proteins. PARP-1, the most characterized
of these polymerases, is critical to the cellular response to
DNA injury.1 Selective binding of PARP-1 to sites of both
single and double strand DNA damage ultimately results in
the repair of the break. ABT-472 (11), an inhibitor of PARP-
1, has been advanced for clinical evaluation as a potentiator
of DNA damaging radio- and chemotherapy agents.2 In order
to obtain in ViVo efficacy of ABT-472, an efficient, scalable
synthetic route is needed. In this paper we report on the
development of a route to ABT-472.
To circumvent the instability of 14 in the presence of acid,
we focused on isolation of the potassium salt 3 (Scheme 2).
The potassium salt had the favorable properties of being a
crystalline, nonhygroscopic solid that could be used directly
in the subsequent Hofmann rearrangement, and 3 could be
easily recovered by crystallization from isopropanol.11 Ad-
dition of KOH to the crude reaction mixture followed by
solvent exchange into isopropanol gave an 86% isolated yield
of 3 with 99.8% purity.
The Hofmann rearrangement (Scheme 3) has usually been
accomplished by addition of an amide to a solution of freshly
prepared potassium hypobromite followed by heating,12
although direct addition of bromine to an aqueous KOH
solution of the amide has been preferred to avoid concerns
regarding stability of the hypobromite.13 Calorimetry during
the direct addition procedure showed an exotherm of -140
Results and Discussion
Our synthesis (Scheme 1) of ABT-472 commenced with
the preparation of anhydride 2 from commercially available
3-nitrophthalic acid (1). As reported,3 dehydration with neat
acetic anhydride at 100-120 °C cleanly yielded the desired
anhydride. Reaction calorimetry showed the dehydration to
be mildly exothermic (-4.1 kcal/mol), however accelerating
rate calorimetry (ARC)4 indicated the potential for an
extremely exothermic decomposition when the mixture was
heated to greater than 100 °C in the presence of metals.5 To
safely control the reaction, the reaction mixture was diluted
with isopropyl acetate, raising the initiation point to >140
(5) (a) Tests were carried out in the presence of 316 stainless steel and titanium.
(b) Explosions with nitric acid/acetic anhydride mixtures have been reported
(Eaborn, C. J. Organomet. Chem. 1978, 144, 271. Andreozzi, R.; Marotta,
R.; Sanchirico, R. J. Haz. Matls. 2002, 90, 111. Chervin, S.; Bodman, G.
T.; Barnhart, R. W. J. Haz. Matls. 2006, 130, 48); however we are unaware
of any examples of hazardous decompositions of aromatic nitro compounds
in the presence of acetic anhydride. The mechanism of destabilization by
metals is not known.
(6) Ritzeler, O.; Stilz, H. U.; Neises, B.; Bock, W. J., Jr.; Walser, A.; Flynn,
G. A. Preparation of benzimidazolecarboxylic acid amino acid amides as
IκB kinase inhibitors. PCT Int. Appl. (2001), WO 2001000610 A1
20010104.
(7) Oku, A.; Matsui, A. Bull. Chem. Soc. Jpn. 1977, 50, 3338.
(8) The regioisomer 13 was identified by 13C NMR analysis and LC/MS.
(9) Ratio is area % based on HPLC. Variances in ratio due to sampling errors
of the heterogeneous mixture were often observed.
(10) Ammonia in THF, DME, MeOH, and IPA gave ratios of 12:13 ranging
from 32:1 to 14:1.
* To whom correspondence should be addressed. E-mail: bruce.gaede@
abbott.com.Telephone: 847-938-0730. Fax: 847-938-2258.
† Current address: Amgen, Inc., Thousand Oaks, CA 91320.
(1) Curr. Med. Chem. 2003, 10, 321.
(2) Lubisch, W.; Kock, M.; Hoger, T.; Schult, S.; Grandel, R.; Muller, R.
Preparation of benzimidazolecarboxamides as poly(ADP-ribose)polymerase
inhibitors. PCT Int. Appl. (2000), WO 2000032579 A1 20000608.
(3) Organic Synthesis, CollectiVe Volume 1; Wiley: New York, 1932; p 402.
(4) Hoppe, T. Chem. Eng. Prog. 1992, 88, 70.
(11) Potassium salt 3 had a solubility of 15 mg/mL (reported as the free acid) in
22% water/IPA at 0 to 5 °C, while the potassium salt of the regioisomer 13
had a solubility of >20 mg/mL under the same conditions.
(12) Wallis, E. S.; Lane, J. F. Organic Reactions, Vol. 3; p 267.
(13) Beckwith, R. C.; Margerum, D. W. Inorg. Chem. 1997, 36 (17), 3754.
10.1021/op7000194 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/15/2007
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Scheme 1. Scaled up route to ABT-472a
a Reagents and conditions: (a) Ac2O, i-PAc, 80 °C; (b) 28% NH4OH, KOH, i-PrOH; (c) (i) KOH, Br2, 0° to 70 °C; (ii) Concd HCl; (d) (i) SOCl2, DME, 50 °C;
(ii) NH4OH; (e) (i) Raney Ni, H2, EtOAc/EtOH; (ii) HCl/EtOAc; (f) EtCHO, EtOH, Pd-C, H2; (g) CDI, NMP, THF; (h) (i) AcOH, H2O; (ii) NaOH; (i) Succinic Acid,
IPA, i-PAc.
Scheme 2. Ammonolysis of 3-nitrophthalic anhydride
The only major impurity identified after the rearrangement
was the brominated arene 16. Formation of 16 proved
sensitive to the potassium hydroxide stoichiometry. With 5
equiv of base, the reaction yielded a 0.1:0.3:99.5 ratio of
3:16:4, whereas with 3 equiv of base the ratio was 5.0:11.3:
83.7. Presumably an excess of base reduces the concentration
of protonated N-bromo amide 15 during the reaction.16
The reaction mixture was held at >60 °C to ensure
destruction of residual potassium hypobromite as well as
bromate and bromite byproducts, since acid quenching prior
to complete decomposition of the oxidants also resulted in
brominated impurity 16.17 Quenching with aqueous HCl after
1 h at 75 °C decomposed the intermediates and precipitated
the desired nitroaniline 4 in 89% yield and >99% purity.
The carboxylic acid in 4 was converted to the corresponding
acid chloride18 with thionyl chloride in DME, followed by
an ammonium hydroxide quench to form amide 5 in 85-
93% yield.
Scheme 3. Step 3 reaction and byproducts
(14) Calculated exotherms were obtained from ChemDraw software (Cambridge-
Soft Corporation, 100 Cambridge Park Drive, Cambridge, MA 02140,
www.cambridgesoft.com). The exotherms also comparable to previously
measured exotherms for N-bromination of amides. See: Amato, J. S.;
Bagner, C.; Cvetovich, R. J.; Gomolka, S.; Hartner, F. W.; Reimer, R. J.
Org. Chem. 1998, 63, 9533.
(15) (a) Denny, W. A.; Rewcastle, G. W.; Baguley, B. C. J. Med. Chem. 1990,
33, 814. (b) Nagasaka, T.; Koseki, Y. J. Org. Chem. 1998, 63, 6797.
(16) N-Bromoamides are known brominating agents, similar to NBS in the
Wohl-Ziegler reaction. For example, see: Park, J. D.; Lycan, W. R.; Lacher,
J. R. J. Am. Chem. Soc. 1954, 76, 1388.
(17) For example, see: Groweiss, A. Org. Process Res. DeV. 2000, 4 (1), 30.
Kajigaeshi, S.; Nakagawa, T.; Fujisaki, S. Chem. Lett. 1984, 2045.
(18) (a) Breslin, H. J.; Kukla, M. J.; Ludovici, D. W.; Mohrbacher, R.; Ho, W.;
Miranda, M.; Rodgers, J. D.; Hitchens, T. K.; Leo, G.; et al. J. Med. Chem.
1995, 38, 771. (b) Kukla, M. J.; Breslin, H. J.; Raeymaekers, A. H. M.;
Van Gelder, J. L.; Janssen, P. A. Preparation of antiViral tetrahydroimidazo-
[1,4]benzodiazepin-2-thiones, Eur. Pat. Appl. (1990), EP 384522 A1
19900829.
kJ/mol, consistent with the calculated exotherm for formation
of the N-bromoamide 15.14 Further heating to 75 °C gave a
single thermal event corresponding to -761 kJ/mol. Analysis
during the heating by both in situ IR and NMR suggested
the individual steps of the rearrangement sequence could not
be separated, and thus the heating was carried out slowly to
control the temperature rise.15
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Scheme 4. Coupling of the piperidine and diamine portions
Initially the nitro group was reduced with palladium on
carbon in THF/methanol, and the resulting diamine was
isolated as the bis-hydrochloride salt 6. A significant impurity
(4-12%) tentatively identified as a dimeric hydrazine (M
+ 1 ) m/e 299 by APCI LC-MS) proved difficult to avoid
or remove. Alternatively, Raney nickel in ethyl acetate/
ethanol cleanly gave the diamine, which was not isolated
but converted to the same bis-hydrochloride salt 6 in 86-
90% yield and >99% purity with no hydrazinyl impurities
observed.19
of residual nickel. The nickel concentrations were found to
correlate to the time between purging of the hydrogen and
filtration of the catalyst, suggesting an instability of the
catalyst matrix to the reaction mixture.
No comparable leaching effect was found with palladium
on carbon. Thus, addition of propionaldehyde (1.5 equiv)21
over 4.5 h to an ethanolic solution of acid 7 at ambient
temperature and 40 psi hydrogen pressure yielded the desired
acid 8 in 86-93% isolated yield, >98% purity, with less
than 10 ppm of Pd.
Piperidine acid 8 was prepared via reductive alkylation
of isonipecotic acid 7 using Raney nickel, but varying
amounts (2-20 mol %) of the N-2-methylpentyl impurity
17 were identified in the crude reaction mixtures. Similar
aldehyde condensations via imines have been reported20 and
clearly were a problem in this reductive alkylation. In order
to favor the desired reaction pathway, the catalyst loading
was increased to 100 wt % Raney nickel and the propion-
aldehyde (1.2 equiv) was added in a controlled fashion over
several hours to limit aldehyde concentration in the presence
of enamine 18. This technique yielded 8 in 89-93% isolated
The coupling of the piperidine acid 8 and the diamine 6
to form the amide 9 via the acylimidazole 19 (Scheme 4a)
gave 9 in good yield by slowly adding 19 to a solution of 6.
A single-crystal X-ray confirmed the regiochemistry of the
coupling (Figure 1). The main competing pathway was
formation of the bis-amide 20. Examination of the reaction
course revealed that 20 was formed during the early part of
the addition of acylimidazolide 19. Presumably in the
presence of substoichiometric amounts of base, the mono-
hydrochloride salt 21 was selectively acylated at the 2-amino
position. While this theory accounted for the observed
product distributions, we have not been able to prepare or
observe the 2-acyl intermediate 22 (Scheme 4b) or demon-
strate its conversion to 20. In order to avoid formation of
this byproduct a solution of diamine dihydrochloride 6 was
added to a solution of acylimidazole 19 and imidazole (from
reaction of CDI with 8), resulting in selective reaction at
the more reactive 3-amino group to give 9 in 95% yield and
99.2% purity.22
yield and reduced the impurity 17 to undetectable levels.
The hydrochloride salt 9 was dissolved in water containing
2.5 equiv of acetic acid and refluxed until cyclization was
complete. Isolation of the cyclized product as the free base
However, isolated product contained up to 1800 ppm levels
(19) (a) Hattori, K.; Yamamoto, H.; Mukoyoshi, K.; Kuroda, S. Preparation of
quinoxalinecarboxamides which haVe poly(adenosine 5′-diphospho-ribose)-
polymerase inhibitory action. PCT Int. Appl. (2003), WO 2003007959 A1
20030130. (b) Lubisch, W.; Kock, M.; Hoger, T. Preparation of 2-phenyl-
benzimidazoles as poly(ADP-ribose) polymerase inhibitors. PCT Int. Appl.
(2000), 2000026192 A1 20000511.
(21) 1.5 equiv of propionaldehyde were necessary with Pd/C to allow for the
competitive reduction of the propionaldehyde by the catalyst.
(22) When the diamine bis-hydrochloride 6 was deprotonated in situ with
imidazole prior to addition of 19, the desired amide 9 was formed with
minimal formation (0.32%) of 20.
(20) List, B., et. al. J. Am. Chem Soc. 2000, 122 (10), 2395-2396. (b) Pollack,
R. M.; Ritterstein, S. J. Am. Chem. Soc. 1972, 94, 5064-5069.
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Figure 1. ORTEP diagram of amide HCl salt 9 dihydrate.
10 was accomplished in 86% yield and 96.2% purity by
neutralization with sodium hydroxide.
Salt screening resulted in selection of the succinate salt
11.23 The salt was crystallized by addition of isopropyl
acetate antisolvent to a methanol solution of the salt at 47
°C, resulting in a 79% yield of 11.
not more than 50 °C to reduce the volume to approximately
90 L. The internal temperature was adjusted to not more than
30 °C, and isopropanol (76 kg) was added to the mixture.
The mixture was distilled under vacuum with a jacket
temperature of not more than 50 °C to approximately 90 L.
The internal temperature was again adjusted to not more than
30 °C and sampled to assay the isopropanol/water ratio.
Isopropanol (76 kg) was added to the mixture to give a water/
isopropanol ratio of not more than 0.22 (wt/wt), and the
resulting slurry was mixed for not less than 1 h. The slurry
was cooled to 0 °C and mixed for not less than 1 h until the
supernatant was less than 20 mg/mL product. The batch was
filtered, and the wet cake was washed with isopropanol (94
kg). The wet cake was purged with nitrogen for not less than
1 h and dried at 45 °C until the loss by TGA was not more
than 5 wt % for isopropanol. Yield: 40.7 kg (86% assay
adjusted yield).
2-Amino-3-nitrobenzoic Acid (4). A 190 L glass-lined
reactor was purged with nitrogen and charged with a solution
of 13.0 kg of potassium hydroxide (232 mol, 5 equiv) in
110 kg of distilled water. The solution was cooled to 15 (
5 °C, and 3 (11.0 kg, 46.5 mol) was then charged to the
reactor. The resulting solution was cooled to 0 ( 5 °C, and
bromine (7.4 kg, 46.4 mol, 1.0 equiv) was slowly added to
the reactor using residual vacuum through Teflon tubing with
a valve to control the addition rate. The internal temperature
of the reaction was kept at not more than 5 °C during the
addition. The mixture was kept at 0 ( 5 °C for not less than
30 min and sampled for analysis.24 The reaction mixture was
heated to 75 ( 5° C at a rate of approximately18 °C/h. Once
at temperature, the mixture was heated for not less than 1 h.
The reaction mixture was cooled to 50 °C, and concentrated
hydrochloric acid (approximately 21.5 kg, 218 mol, 4.7
equiv) was slowly added to the reaction mixture to adjust
the pH to less than 2.5 at a rate to control evolution of carbon
dioxide. The resulting yellow slurry was cooled to 20 °C
and mixed not less than 1 h. Once analysis of the supernatant
showed not more than 2 mg/mL of product, the material was
filtered. The filter cake was washed with water until the
bromide/chloride content in the wash was not more than 0.1
mg/mL (>100 kg of water was required). The wet cake was
Conclusions
ABT-472 was prepared in 32-35% overall yield in nine
transformations. By evaluating the root cause of formation
of impurities, the purity of the final product was controlled
to >99.5%.
Experimental Section
3-Nitrophthalic Anhydride (2). A 100 L glass round-
bottom flask was purged with nitrogen and charged with 25.0
kg of 3-nitrophthalic acid (1, 118.4 mol) and isopropyl
acetate (21.7 kg). To the 100 L flask was charged acetic
anhydride (25.4 kg, 249 mol, 2.1 equiv). The bath temper-
ature was raised to 60 ( 5 °C, and the contents were stirred
with the bath at 60 ( 5 °C until HPLC analysis showed not
more than 2% starting material remaining. The slurry was
transferred to a 30 gal glass-lined reactor with heptane (34.0
kg) used as a rinse and transferring agent, and the contents
were cooled to 0 ( 5 °C. Once analysis of the supernatant
showed less than 15 mg/mL of product, the material was
filtered and the cake was washed with MTBE (78 kg) until
analysis showed less than 1% acetic acid in the wash. The
wet cake was dried at 55 ( 5 °C for 3 days until the loss by
TGA was less than 1% for MTBE. Yield: 20.3 kg (86.0%
assay adjusted yield).
2-(Aminocarbonyl)-3-nitrobenzoic Acid Potassium Salt
(3). A nitrogen purged 115 L glass-lined reactor was charged
with 28 wt % NH4OH (65.6 kg, 525 mol). The reactor was
cooled to 0 ( 5 °C, and 3-nitrophthalic anhydride (2) (38.4
kg, 200.9 mol) was charged over 2.5 h as a solid while
maintaining the internal temperature below 15 °C. The
internal temperature was adjusted to 20 ( 5 °C, and a
solution of KOH (12.4 kg, 221.4 mol, 1.1 equiv) in water
(19.4 kg) was added to the reaction mixture. The contents
were distilled under vacuum with a jacket temperature of
(23) Handbook of Pharmaceutical Salts: Properties, Selection and Use,
International Union of Pure and Applied Chemistry (IUPAC); Stahl, H. P.,
Wermuth, C. G., Eds.; Wiley-VCH: New York, 2002.
(24) A sample is heated to >60° C for not less than 5 min and then assayed
using HPLC. The sample is considered to pass when less than 2 area % of
3 remains. Additional bromine could be added should the sample fail.
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dried under vacuum at not more than 70 °C using a nitrogen
bleed. The drying was considered complete when water
determined by Karl Fischer titration was not more than 0.5%
by weight. Yield: 7.6 kg (90% assay adjusted yield).
2-Amino-3-nitrobenzamide (5). A solution of 4 (6.0 kg,
32.9 mol) in DME (33 kg) was prepared and filtered into a
100 L glass round-bottom flask using DME (4 kg) as a rinse.
The combined solution was sampled and checked for water
content by Karl Fischer titration.25 Thionyl chloride (5.2 kg,
43.7 mol, 1.33 equiv) was added to the solution while
stirring; the reaction was mildly exothermic (ATR (Adiabatic
Temperature Rise) ) 7.7 °C). The reaction solution was then
warmed to 50 ( 5 °C and stirred for not less than 12 h or
until analysis showed the reaction was complete. The reaction
was sampled, and an aliquot was reacted with 0.5 M
ammonia in dioxane for 30 min prior to HPLC analysis. The
reaction was considered complete if less than 1.0 PA% of
starting material was detected. The reaction mixture was
cooled to 25 ( 5 °C and slowly added to 28 wt % NH4OH
(42 kg, 715 mol, 22 equiv) in a 190 L glass-lined reactor,
while the temperature was maintained at not more than 40
°C. Safety Note: The reaction was strongly exothermic (ATR
) 68 °C) and eVolVed a large Volume of gas. DME (2 kg)
was used to rinse the flask. Orange solids precipitated out
immediately. The mixture was warmed to 50 ( 5 °C and
stirred for not less than 2 h. Water (47 kg) was added, and
the mixture was warmed to 50 ( 5 °C and stirred for another
2 h. The slurry was cooled to 25 ( 5 °C and stirred for not
less than 6 h or until the concentration of product in the
supernatant was less than 1.0 mg/mL. The orange product
was filtered and washed with water until the last wash had
not more than 5 ppm of ammonium ion by IC analysis. A
large variability was observed in the amount of water
required over three runs: Run 1, 382 kg; Run 2, 181 kg;
Run 3, 272 kg. The filter cake was washed with isopropyl
alcohol (not less than 19 kg) to remove residual water, and
then the wet cake was dried under vacuum at not more than
65 °C, for not less than 12 h. Drying was considered
complete when the loss by TGA was less than 1.0% for
isopropanol. Yield: 5.25-5.75 kg for three runs (85-93%
assay adjusted yield).
sampled and analyzed for completion. The sample passed
when not more than 1.0 area % of starting material remained.
The reactor was then pressure purged with nitrogen, and the
contents were filtered through a bed of diatomaceous earth
filter aid with backup filters. Ethyl acetate (60 kg) was
charged to the reactor as a rinse and passed through the
filters. Hydrogen chloride gas (8.4 kg, 230 mol) was added
to the combined filtrates, while a reaction temperature of
not more than 30 °C was maintained with cooling (ATR )
10 °C). The precipitated salt was mixed for 75 min, and a
sample was taken to confirm that the pH was not more than
2. The slurry was filtered to collect a white solid, which was
washed with ethyl acetate (152 kg). The wet cake was dried
in a hastelloy dryer under vacuum for 16 h at 50 °C. Drying
was considered complete when the loss by TGA was less
than 1.0% for water. Yield: 19.08 kg (95.5% assay adjusted
yield).
1-(1-Propyl)-piperidine-4-carboxylic Acid (8). A 180
L glass lined pressure reactor was pressure checked with
nitrogen. Catalyst (5% palladium on carbon (50 wt % water
wet, 3.0 kg, 10 wt % on dry basis), piperidine 7 (14.8 kg,
114.6 mol), and ethanol 2B (83 kg, 7 L/kg starting material)
were charged to the reactor. A pressure canister was charged
with propionaldehyde (12.0 kg, 206.6 mol, 1.8 equiv) and
pressure purged with nitrogen before it was pressurized to
55 psi with nitrogen. The reactor was pressure purged three
times with hydrogen and pressurized to 40 psi with hydrogen.
Propionaldehyde from the pressure canister was added slowly
to the reactor over 4.5 h, while a temperature of 25 ( 5 °C
was maintained with cooling (ATR ) 57 °C). The contents
of the reactor were stirred a further 2 h under 40 psi hydrogen
before sampling for completion. The reaction was held under
hydrogen pressure until analysis showed less than 1.0 PA%
starting material. An aliquot was derivatized with BSA (1
mL/10 mg 8) and analyzed by GC. The reactor was then
pressure purged with nitrogen, and the contents were filtered
through a bed of filter aid with backup filters. Ethanol 2B
(17 kg) was twice charged to the reactor and passed through
the filters. The combined filtrates were concentrated under
vacuum at not more than 50 °C internal temperature to
approximately 73 L. Isopropyl acetate (105 kg) was added,
and the mixture was again concentrated under vacuum at
not more than 50 °C internal temperature to approximately
73 L. This was repeated for a total of 3 times. During the
second distillation the product started to crystallize out and
remained as a slurry for the remaining distillation. Isopropyl
acetate (130 kg) was added, and the solution was stirred at
25 °C under nitrogen for approximately 7 h. A sample was
checked for supernatant concentration of not more than 2.0
mg/mL. The product was filtered and washed with two
portions of isopropyl acetate (35 kg, 38 kg). The wet cake
was dried under vacuum at not more than 65 °C for not less
than 12 h. A dryer sample was assayed for isopropyl acetate.
Drying was considered complete when a sample showed less
than 0.5% w/w isopropyl acetate. Yield: 17.8 kg (90% assay
adjusted yield).
2,3-Diaminobenzamide Bis-hydrochloride (6). A 550
L glass-lined pressure reactor was pressure checked and was
purged with nitrogen. Raney Nickel (W. R. Grace 2800, 6.0
kg wet slurry) was charged to the reactor followed by water
(0.3 kg) to rinse the catalyst into the reactor. Ethanol 2B
(20.2 kg) was added to the reactor and mixed to disperse
water. A slurry of 5 (16.0 kg, 88.3 mol) and ethyl acetate
(161 kg) was transferred to the reactor, and additional ethyl
acetate (200 kg) was used to rinse the substrate into the
reactor. The reactor was pressure purged three times with
hydrogen and pressurized to 40 psig with hydrogen. Agitation
was increased to initiate the reaction. The reaction exotherm
was allowed to increase to 40 °C and was held at this
temperature (ATR ) 52 °C) with cooling for 100 min, at
which point hydrogen consumption ceased. The reaction was
(25) Water content of 0.02 to 0.04% w/w was determined for three runs (0.015
to 0.029 equiv of water). The thionyl chloride charge is adjusted to ensure
that more than 1 equiv relative to the sum of substrate and water is added.
1-Methyl-piperidine-4-carboxylic Acid (2-Amino-3-
carbamoyl-phenyl)-amide Hydrochloride (9). To a 100 L
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flask was charged carbonyldiimidazole (CDI) (7.7 kg, 47.5
mol) and anhydrous NMP (40 kg) under nitrogen. Dissolution
was endothermic, and the mixture was warmed to 25 °C to
dissolve solids. To a 110 L glass lined reactor was charged
8 (8.2 kg, 47.9 mol) and anhydrous NMP (9 kg), and the
resulting slurry was stirred. The CDI solution was added to
the slurry of 8 at a rate to control gas evolution. The reaction
was slightly endothermic (ATR ) -4 °C). When addition
was complete, the flask was rinsed with anhydrous NMP (2
kg) and stirred 1 h at room temperature. After 1 h the reaction
was sampled. A weighed aliquot was added to excess
benzylamine in acetonitrile (sample/benzylamine/acetonitrile
1:1:2 v/v/v) and allowed to react for 30 min prior to HPLC
analysis. Reaction was considered complete when the yield
of benzylamine amide was >90%. The solution was heated
to 50 °C. In a separate 100 L flask, 6 (8.9 kg, 39.7 mol) was
dissolved in anhydrous NMP (49 kg) with heating to not
more than 30 °C. The resulting solution of 6 was transferred
to the solution of acylimidazole, and the temperature was
allowed to rise through a mild exotherm (ATR ) 22 °C).
The reaction was stirred at 50 °C for 18-24 h until 6 was
not more than 3 area % of the product peak by HPLC at
210 nm. Product precipitated during the course of the
reaction. The contents of the reactor were cooled to room
temperature and transferred to a 50 gal reactor using a rinse
of NMP (5 kg). To the slurry was added 71 kg of THF to
complete the precipitation. The mixture was stirred at room
temperature until the concentration of product in the super-
natant was not more than 2 mg/mL. The product was filtered.
The filter cake was washed with agitation using 10% w/w
water in n-butanol in portions until the wash liquors had not
more than 10 mg/mL NMP. The product was dried under
vacuum at not more than 50 °C until solvent levels were
not more than 1% NMP and not more than 1% n-butanol.
Yield: 11.8 kg (86% assay adjusted yield).
supernatant concentration of not more than 1 mg/mL. The
product was isolated in a filter dryer and washed with water
until sodium in the wash liquors was not more than 20 µg/
mL. The product was dried in the filter dryer under vacuum
at 50 °C until the water content was not more than 3 wt %
by Karl Fischer titration. Yield: 8.2 kg (86% assay adjusted
yield).
2-(1-Propyl-4-piperidinyl)-1H-benzimidazole-4-car-
boxamide Succinate Salt (11). A solution of 10 (7.8 kg,
27.3 mol) and succinic acid (3.55 kg, 30.1 mol) in methanol
(36 kg) was heated to 60 °C for 30 min. The solution was
filtered into a 115 L glass lined reactor, and isopropyl acetate
(10.8 kg) was added to the reactor. The solution was held at
50 °C for 30 min, and then the temperature was reduced to
47 °C.
Seed crystals of 11 (0.11 kg) were slurried in isopropyl
acetate (1.0 kg) in a 4 L pressure canister and transferred to
the reactor with a rinse of isopropyl acetate (0.5 kg). The
reactor was held at 47 °C for 3 h, and isopropyl acetate (7.2
kg) was added to the reactor via a subsurface addition tube
at 0.7 kg/min. The slurry was mixed for 1 h. Additional
isopropyl acetate (7.2 kg) was added to the reactor in the
same manner, and the slurry was mixed for 1 h. Isopropyl
acetate (28.8 kg) was again added to the reactor in the same
manner, and the slurry was held overnight at 47 °C. The
slurry was cooled to 25 °C over 1 h and isolated in an
agitated filter. The cake was washed with 1:2 w/w methanol-
isopropyl acetate (60 kg) followed by isopropyl alcohol (84
kg). The wet cake was blown dry for 1 h in the filter and
dried under vacuum at 50 °C overnight using a tray dryer.
Drying was considered to be complete when the solid
contained not more than 0.5 wt % of isopropanol and
isopropyl acetate and not more than 0.3 wt % of methanol.
The dried product was milled using a Fitzmill. Yield: 8.53
kg (premilling) (79% assay adjusted yield).
2-(1-Propyl-4-piperidinyl)-1H-benzimidazole-4-car-
boxamide (10). A solution of water (60 kg) and glacial acetic
(5.4 kg) acid was prepared. To a reactor was charged 9
(11 kg, 32.2 mol), and the solid was dissolved in 55 kg of
the acetic acid solution with heating under nitrogen. The
solution was filtered into a 115 L glass lined reactor, and
the remainder of the acetic acid solution was used as a rinse.
The solution was heated to reflux for 4 h (reaction was
endothermic), and a sample was taken. Reaction was
continued until 9 was not more than 1 area % of the product
by HPLC. The reaction was cooled to 20 °C, and the pH of
the solution was adjusted to less than 12 by addition of 50%
sodium hydroxide. Product precipitated during the addition.
The reaction temperature was allowed to rise during the
sodium hydroxide addition (ATR ) 41 °C). The reaction
was cooled to not more than 25 °C and stirred for 1 h. The
slurry was checked for completion of precipitation with a
Acknowledgment
The authors thank Dr. Nancy Benz, Mr. Michael Moore,
Ms. Christine Havrilla, and Dr. Thomas Gray of Abbott
Laboratories for analytical method development and as-
sistance. The authors also thank Shan Lin and Dr. Zhe Wang
of Abbott Laboratories for the ARC data.
Supporting Information Available
X-ray crystal data for 9. Optimization of stoichiometry
for steps 2 and 3; optimization of reagent for step 3. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Received for review January 26, 2007.
OP7000194
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Vol. 11, No. 4, 2007 / Organic Process Research & Development