Organic Process Research & Development
ARTICLE
was obtained. The yield (42.3%) of the product was comparable to
those of laboratory runs (yield: 40À50%).
dryer under reduced pressure at 60 °C. By this procedure, 9.25 kg
1
of alcohol (6) was obtained (isolated 42.3%). Mp 125 °C; H
MNR (300 MHz, CDCl3) δ 6.29 (s, 1H), 4.05À3.90 (m, 2H),
3.83 (t, J = 6.0 Hz, 2H), 2.95À2.80 (m,2H), 2.75À2.65 (m, 4H),
1.88 (t, J = 6.0 Hz, 2H), 1.80À1.60 (m, 8H), 1.46 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 154.68, 79.52, 59.86, 56.80,
44.36, 30,58, 29.74, 28.50, 23.42.
’ CONCLUSION
A safe, scalable process including Reformatsky reaction was
applied to pilot manufacturing of tert-butyl-4-(2-hydroxyethyl)-
4-(pyrrolidin-1-yl)-piperidine-1-carboxylate (6), which is an inter-
mediate of novel antiarteriosclerotics (1). Iminium salt formation
was successfully achieved by TFA, and the reaction heat could be
successfully controlled by slow addition of methyl bromoacetate.
This led to successful scale-up manufacturing to a scale of 15 kg.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR of
S
b
compound (6) and copies of HPLC results. This material is available
’ EXPERIMENTAL SECTION
’ AUTHOR INFORMATION
NMR spectra were measured on a Varian MERCURY-300VX.
High-performance liquid chromatographic (HPLC) analysis was
carried out using a Shimadzu LC-10ADVP.
Corresponding Author
*E-mail: hiroshi.oosato@shionogi.co.jp.
Procedure for Manufacturing Alcohol (6) in a Pilot Plant.
Enamine Formation and Iminium Salt Formation. N-Boc-piper-
idone (2) (15.0 kg, 75.3 mol) was dissolved in THF (85 L) at
25 °C, and pyrrolidine (10.7 kg, 150.6 mol) was added to the
THF solution. This reaction mixture was heated azeotropically
over 3 h. After the confirmation of the absence of starting material
by NMR and the absence of the water by a Karl Fischer test, this
enamine solution was cooled to 5 °C, and TFA (10.3 kg, 90.4 mol)
was added dropwise over 1 h at below 5 °C. This iminium salt
solution was used for Reformatsky reaction without purification.
Zinc Activation, Reformatsky Reaction, and Red-Al reduc-
tion. 1,2-Dibromoethane (2.8 kg, 15.1 mol) was added to a slurry
of zinc (7.4 kg, 112.9 mol) in THF (100 L), and this mixture was
refluxed for 3 h. The absence of 1,2-dibromoethane was con-
firmed by GC, and this slurry was cooled to 5 °C. Iminium salt
solution was added to activated zinc slurry at below 10 °C, and
methyl bromoacetate (20.7 kg, 135.5 mol) was added dropwise
over 2 h at below 5 °C. The mixture was aged for 1 h at the same
temperature. After the completion of the reaction had been con-
firmed by HPLC, Red-Al (65.4 kg, 323.7 mol) in toluene (112 L)
was added dropwise over 3 h. After the completion of the reaction
had been confirmed by HPLC, acetone (15.7 kg, 271.0 mol) was
added to the reaction mixture at the same temperature.
Quenching and Isolation of Alcohol (6). The reaction mixture
was poured into a solution of citric acid hydrate (84.0 kg, 399.7 mol)
in water (210 L) dropwise over 2 h at below 5 °C. The pH of the
aqueous layer was adjusted to 10 with aqueous 48% NaOH, and
then the mixture was warmed to 20 °C. The organic layer was
separated and washed subsequently with aqueous 1% NaOH
(150 kg) and water (150 kg). The organic layer was extracted by
aqueous 19% citric acid solution (2 Â 33 kg), and a combined
aqueous layer was diluted by ethyl acetate (65 L). The pH of the
aqueous layer was adjusted to 10 with aqueous 10% NaOH, and
then the separated organic layer was washed by aqueous 5% NaCl
and evaporated to around 40 L. MeOH (45 L) was added to the
residue, and this mixture was evaporated to around 40 L. This
procedure was repeated to remove ethyl acetate. After less than
1 wt % of ethyl acetate was confirmed by GC, MeOH (30 L) and
water (30 L) were added to the solution at 20 °C, and the alcohol
(6) was observed to precipitate. This slurry was cooled to 5 °C
and aged for 3 h. The mixture of water (36 L) and MeOH (9 L)
was added dropwise over 3 h to the slurry at 5 °C and aged for
30 min. Water (45 L) was added dropwise over 1 h and aged for
30 min. The crystals were filtrated, washed by the mixture of
water (81 L) and MeOH (9 L), and dried using a double-cone
’ ACKNOWLEDGMENT
We thank Natsuko Suzuki, Yutaka Yokota, and Dr. Yoshinori
Murata in Shionogi CMC development laboratories for helpful
discussion on process development studies.
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’ NOTE ADDED AFTER ASAP PUBLICATION
This paper was published on the Web on August 15, 2011.
Additional corrections were made in the Abstract, Results and
Discussion, and Experimental sections. The corrected version
was reposted on August 31, 2011.
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dx.doi.org/10.1021/op2001723 |Org. Process Res. Dev. 2011, 15, 1433–1437