Organic Process Research & Development
ARTICLE
Hastelloy reactor equipped with a pressure relief valve, rupture
disk (10 bar), hollow shaft turbine agitator, Buchi Pressure
Control (BPC) unit, Pt100 thermocouple, recirculating heater/
chiller, and knockout tank. After grounding and blanketing with
nitrogen, 10% Pd/C (61.1 g, 50% wet) in MeOH (1.0 L) and 9
(599.8 g, 1.84 mol) in MeOH (5.0 L) along with 3.0 L of
additional MeOH were charged to the reactor. A leak test and
nitrogen purge were conducted. Hydrogen was charged via the
BPC at 2.76 bar (40 psi) and 35À55 °C until complete and then
held at 2.76 bar (40 psi) at 20 °C overnight. Hydrogen was
vented with a nitrogen purge. Catalyst was removed by filtration
through Celite 545. The filtrate was charged to a reactor, and
conc HCl (175 mL, 77.7 g, 2.13 mol, 1.15 equiv) was added. The
batch was heated to 60À65 °C for 2 h and cooled to 20À22 °C,
and 70% of the solvent was removed by vacuum distillation
(50À100 mbar). THF (11.1 L) was added using the cubic
formula V(t) = Vtotal(t/ttotal)3 to precipitate the product, and
the brown to deep purple solids were isolated by vacuum
filtration, washed with 200 g of MeOH/THF (weight ratio
1:9), and dried to constant weight in a vacuum oven at
35À40 °C yielding a light coffee-colored solid (490.1 g, 1.72
each of water and acetone, and then dried to constant weight in a
vacuum oven at 35 °C to give a white solid (626 g, 76% yield)
with a purity of 99.9 A%. 1H NMR (400 MHz, DMSO-d6) δ 12.3
(br s, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.89
(dd, J = 9.3, 2.3 Hz, 1H), 3.90 (s, 3H), 3.80 (m, 8H), 3.14 (t, J =
7.6 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 2.01 (quint, J = 7.6 Hz, 2H);
LC/MS (ESI, m/z) 358.2 Da (M + 1).
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectroscopy
b
traces for some of the compounds. This material is available free
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jchen@cephalon.com.
’ ACKNOWLEDGMENT
1
We thank Nelson Landmesser for hazards evaluation and
Scott Field, Andrea Pless, Mark Olsen, Gregory Gilmartin, and
Christopher Neville for analytical assistance. We thank Stuart
Dodson for procurement support, James Galloway for EHS advice,
and Robert DeSonier and Carmella Tallarida for helpful discussion
about the hydrogenation equipment setup. We are thankful for
continuous support from our management Michael Christie and
John Mallamo and former management Michael Kress.
mol, 93.6% yield) with 96.0 A% purity. H NMR (400 MHz,
DMSO-d6) δ 7.83 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.27 (d, J =
8.6 Hz, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 3.17 (t, J = 7.7 Hz, 2H),
2.53 (t, J = 7.3 Hz, 2H, overlapped partially with DMSO), 2.07
(quint, J = 7.5 Hz, 2H); LC/MS (ESI, m/z) 248 (M + 1).
Preparation of 4-{5-[Bis(2-chloro-ethyl)-amino]-1-meth-
yl-1H-benzoimidazol-2-yl}-butyric Acid Methyl Ester (11).
A mixture of 10 (400 g, 1.41 mol, 1.0 equiv), chloroacetic acid
(2.8 kg, 28.6 mol, 21 equiv), and THF (1.4 L, 3.5 volumes) was
stirred to dissolve solids. Borane-THF (1 M, 9.87 L, 9.87 mol, 7.0
equiv) was added over 1À3 h, at 30 to 40 °C. The reaction was
then heated to 48À50 °C, held until complete by HPLC (∼2 h),
cooled to 20 °C, and quenched with MeOH (400 mL), and then
THF was removed in vacuo (50À100 mbar) to leave ∼1/3 of the
original volume as a brown to black oily residue. The product was
precipitated by adding DI water (2.25 L) to the residue and
neutralizing to pH 7À8 (K2CO3, satd aq soln) at 10À17 °C. The
solids were isolated by vacuum filtration and then slurried in DI
H2O (4.0 L) at 20À25 °C for 1 h. Isolated solids were dried on
the filter under vacuum at <30 °C. Crude product was treated
with Celite 545 (5 wt %) and Norit Supra carbon (3 wt %) in 20
vol of MTBE at 50 °C for 2 h, distilled after a hot filtration to 5 vol
of MTBE, seeded at 42À48 °C, and cooled to 30À35 °C.
Heptane (5 vol) was charged rapidly, and cooling was continued
to 0À2 °C. The product was isolated by vacuum filtration and
dried to a constant weight in a vacuum oven at 30 °C to yield an
off white solid (453.2 g, 1.22 mmol, 86.4% yield) in 99.2 A%
purity. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 8.8 Hz,
1H), 6.92 (d, J = 2.3 Hz, 1H), 6.78 (dd, J = 8.8, 2.3 Hz, 1H), 3.70
(br s, 8H), 3.66 (s, 3H), 3.59 (s, 3H), 2.83 (t, J = 7.4 Hz, 2H),
2.48 (t, J = 7.4 Hz, 2H, overlapped partially with DMSO), 2.01
(quint, J = 7.4 Hz, 2H); LC/MS (ESI, m/z) 372 (M + 1), mp
60À63 °C dec.
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Preparation of Bendamustine Hydrochloride (1). A 5-L
jacketed glass reaction vessel was charged with 776 g (2.08 mol)
of 11 and conc HCl (3 L) and then heated to reflux for 4 h.
Solvent (70 wt %) was removed at 45À65 °C and 134À165
mbar. DI water (50 °C, 500 mL) was added, and the mixture was
cooled over 5 h to 0À5 °C to crystallize the product. (If
nucleation did not occur in 15 min, 0.1 wt % seed was added.)
The product was isolated by filtration, washed with 1 volume
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dx.doi.org/10.1021/op200176f |Org. Process Res. Dev. 2011, 15, 1063–1072