Organic Process Research & Development
ARTICLE
product were concentrated. To the viscous oil was added
MTBE (1.5 L), and the mixture was warmed to 30ꢀ35 °C with
vigorous stirring. A crystalline suspension began to form, and
then hexanes (1 L) was added. The suspension was stirred for
another 20 min and then was allowed to stand for 30 min before
being filtered. The product 6 was collected as a pale-yellow,
crystalline solid (528 g, 61%). It should be noted that the mother
liquor can be harvested, rechromatographed, and recrystallized
to provide a further 10ꢀ20% yield, if desired. 1H NMR 8.77 (m,
1H), 7.08 (m, 1H), 7.02 (m, 2H), 3.86 (m, 1H), 3.70 (s, 2H),
3.33 (m, 1H), 2.83 (m, 2H), 2.44 (m, 1H), 2.51 (s, 3H), 2.37 (dt,
1H, J = 9.8, 1.8 Hz), 2.33 (m, 1H), 2.30 (s, 3H), 1.73 (m, 3H),
1.53 (m, 1H), 0.94 (d, 3H, J = 6.6 Hz), 0.74 (m, 3H). Purity
99.1% by HPLC.
’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra for 1, 4, 6, 14 and
b
15 are provided. This information is availablefree of chargevia the
’ AUTHOR INFORMATION
Corresponding Author
Present Addresses
†Centre for Drug Research and Development, Suite 364-2259
Lower Mall, University of British Columbia, Vancouver, BC,
Canada V6T 1Z4.
‡Genzyme Corp., 153 2nd Ave., Waltham, MA 02451, United States.
Preparation of 6-Chloro-N-{(R)-3-[4-(3-methoxy-1-thio-
phen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethy-
lnicotinamide (1). Dichloromethane (2 L) was added to a
reactor, and the solvent was cooled to 15 °C. Amine 6 (500 g,
1.15 mol) was then added, rinsing forward with dichloro-
methane (1 L). Carbamate reagent 14 (256 g, 1.21 mol) was
then added, again rinsing forward with dichloromethane (0.5 L).
The mixture formed a pale-yellow suspension. Diisopropylethy-
lamine (240 mL, 1.37 mol) was added over 5 min, rinsing
forward with dichloromethane (0.5 L). At the completion of
addition of the DIPEA, all the solids dissolved. After 60 min, the
’ ACKNOWLEDGMENT
We thank the analytical staff at AnorMED for their method
development and analyses, and scientists at Genzyme Corp. for
their proofreading and assistance with manuscript preparation.
’ REFERENCES
1
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reaction was complete by H NMR aliquot. The reaction was
quenched with water (4 L), and the pH of the aqueous layer was
adjusted to 1ꢀ2 (target 1.5) with slow addition of concentrated
HCl (225 mL). Diethyl ether (8 L) was added, and the organic
and aqueous layers were separated. The aqueous layer was
washed with diethyl ether (3 ꢁ 4 L) to remove the yellow
p-nitrophenol. Dichloromethane (3 L) was added to the aqu-
eous layer, and the pH adjusted to 7 with 4 M NaOH solution
(270 mL). Saturated aqueous sodium bicarbonate (1 L) was
added, and the pH adjusted to 8 with 4 M NaOH (100 mL).
The aqueous and organic layers were separated, and the aqueous
layer washed with dichloromethane (3 L). The combined
organic layers were dried with sodium sulfate and were con-
centrated. The residue was reconstituted in dichloromethane
(50 mL) and was filtered through silica gel (1 kg), which had
been preconditioned with 1% NH4OH, 5% MeOH in ethyl
acetate. The filtration was monitored by TLC, eluting first with
1% NH4OH, 5% MeOH in ethyl acetate, and then 25% MeOH,
10% NH4OH in ethyl acetate, and was intended to remove high-
polarity baseline residual reagents and impurities. The fractions
containing product were then concentrated, taken up in metha-
nol, and concentrated again (to remove ethyl acetate). The
product was dried under vacuum in a 40 °C oven for 48 h to
produce an amorphous light-yellow, foamy solid (1) in a yield
of 563 g (96%). 1H NMR (CDCl3) δ 8.76 (d, 1H, J = 5.5 Hz),
7.38 (dd, 1H, J = 5.0, 3.0 Hz), 7.12 (m, 1H), 7.03 (m, 2H), 6.93
(m, 1H), 4.22 (m, 1H) 3.84 (m, 1H), 3.68 (m, 2H), 3.66 (s, 3H),
3.26 (m, 1H), 2.83 (m, 2H), 2.72 (m, 1H), 2.57 (t, 1H, J = 11.4
Hz), 2.53 (s, 3H), 2.26 (m, 3H), 2.16 (t, 1H, J = 11.4 Hz),
1.76ꢀ1.66 (m, 3H). 1/54 (m, 1H), 1.02 (m, 1H), 0.98 (d, 3H,
J = 6.6 Hz), 0.88 (m, 1H). 13C NMR 167.4, 159.4, 155.7, 150.4,
147.9, 139.1, 133.2, 127.9, 126.4, 122.8, 121.7, 64.6, 60.9, 52.6,
52,1, 43.6, 41.2, 40.5, 31.0, 30.0. 22.4, 19.1, 13.8. MS m/z 508
(m + H). HPLC purity 99.84%. Chiral HPLC purity >99.5% ee.
Anal. Calcd For C24H34N5ClO3S: C, 56.74; H, 6.74; N, 13.78;
Cl, 6.98; S, 6.31. Found: C, 56.94; H, 6.82; N, 13.76; Cl, 7.14;
S, 6.23.
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dx.doi.org/10.1021/op200259t |Org. Process Res. Dev. 2012, 16, 109–116