An efficient scalable process for the synthesis of N-Boc-2-tert-butyldimethylsiloxypyrrole

Article abstract of DOI:10.1021/op025532+

A safe, reliable and scalable process for the preparation of N-Boc-2-tert-butyldimethylsiloxy-pyrrole (TBSOP) is described. In a three-step, one-pot sequence (±)-4-amino-3-hydroxybutyric acid was converted to N-Boc-4-hydroxy-2-pyrrolidinone. This stable crystalline product was isolated by filtration directly from the reaction mixture. Dehydration followed by enolization and silylation produced the target compound without the need for chromatographic purification. The process was demonstrated in the pilot plant to make multikilogram quantities of material in 85% overall yield.

Full text of DOI:10.1021/op025532+

Organic Process Research & Development 2002, 6, 416−418
An Efficient Scalable Process for the Synthesis of
N-Boc-2-tert-butyldimethylsiloxypyrrole
Zhenping Tian,* Michael Rasmussen, and Steven J. Wittenberger
Abbott Laboratories, Global Pharmaceutical Research and DeVelopment, Process R & D, 1401 Sheridan Road,
North Chicago, Illinois 60064-4000, U.S.A.
Scheme 1
Abstract:
A safe, reliable and scalable process for the preparation of
N-Boc-2-tert-butyldimethylsiloxy-pyrrole (TBSOP) is described.
In a three-step, one-pot sequence (()-4-amino-3-hydroxybutyric
acid was converted to N-Boc-4-hydroxy-2-pyrrolidinone. This
stable crystalline product was isolated by filtration directly from
the reaction mixture. Dehydration followed by enolization and
silylation produced the target compound without the need for
chromatographic purification. The process was demonstrated
in the pilot plant to make multikilogram quantities of material
in 85% overall yield.
Introduction
N-Boc-2-tert-butyldimethylsiloxypyrrole (TBSOP) was
introduced nearly a decade ago for the synthesis of homo-
chiral R,â-unsaturated γ-lactams.1 This building block has
been used extensively in the context of vinylogous aldol
reactions,2,3 including an example of a condensation with
an N-acyliminium ion.4 We required multikilogram quantities
of this compound to support the development of a clinical
candidate. The method cited in the literature1 for the
preparation of TBSOP involved the oxidation of pyrrole with
hydrogen peroxide,5 a reaction that raised safety concerns if
done on large scale. Several chromatographic purifications
seemed to be necessary to produce good-quality material.
In this work, we describe an alternate preparation that is safe,
reliable, and amendable to multikilogram-scale production.
group, to yield (()-4-(trimethylsiloxy)-2-pyrrolidinone 2. In
our hands the yields of 2 were variable (60-95%). The
remainder of the material being the des-silyl derivative 3
(Scheme 1) that was thought to be caused by ammonium
chloride mediated desilylation under the reaction conditions.
Buffering the reaction with pyridine (0.05-0.40 equiv)
tightened the yield range to some extent (80-96%). How-
ever, our desire to minimize manipulations and run as many
transformations as possible without isolation led us to explore
conducting the reaction under basic conditions. Exposure of
1 to HMDS and pyridine in refluxing xylene led to a high
yield of 27 (91-98%) and some bis-silylation product 4 (2-
7%). The exclusion of chlorotrimethylsilane from the reaction
allowed for the work up to be simplified to merely
concentration under reduced pressure to remove volatile
reaction byproducts. The residue was dissolved in THF or
isopropyl acetate (iPAc) and treated with di-tert-butyl
dicarbonate and DMAP to introduce the Boc group and give
(()-N-Boc-4-(trimethylsiloxy)-2-pyrrolidinone 5.8 When this
reaction was judged to be complete shown by HPLC analysis
of starting material of less than 1%, triethylamine trihydro-
fluoride (Et3N‚3HF)9 was added to the reaction mixture to
remove the trimethylsilyl moiety. As the deprotection
Results and Discussion
We were prompted by a paper from the Pifferi group
regarding the dehydrative cyclization of (()-4-amino-3-
hydroxybutyric acid 1 with 1,1,1,3,3,3-hexamethyldisilazane
(HMDS) and chlorotrimethylsilane in refluxing xylene.6 The
reaction proceeded with in situ protection of the hydroxyl
(1) (a) Rassu, G.; Casiraghi, G.; Spanu, P.; Pinna, L. Gasparri Fava, G.; Belicchi
Ferrari, M.; Pelosi, G. Tetrahedron: Asymmetry 1992, 3, 1035. (b)
Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. J. Org. Chem. 1992, 57,
3760.
(2) Reviews: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
ReV. 2000, 100, 1929. (b) Rassu, G.; Zanardi, F.; Battistini, L. Casiraghi,
G. Chem. Soc. ReV. 2000, 29, 109. (c) Rassu, G.; Zanardi, F.; Battistini,
L.; Casiraghi, G. Synlett 1999, 1333. (d) Casiraghi, G.; Rassu, G. Synthesis
1995, 607.
(3) Recent examples: (a) Uno, H.; Nishihara, Y.; Mizobe, N.; Ono, N. Bull.
Chem. Soc. Jpn. 1999, 72, 1533. (b) Pichon, M.; Jullian, J.-C.; Figade`re,
B.; Cave´, A. Tetrahedron Lett. 1998, 39, 1755.
(4) Pichon, M.; Figade`re, B.; Cave´, A. Tetrahedron Lett. 1996, 37, 7963.
(5) Bocchi, V.; Chierici, L.; Gardini, G. P.; Mondelli, R. Tetrahedron 1970,
26, 4073.
(7) (()-4-(trimethylsiloxy)-2-pyrrolidinone (2) was prepared and character-
ized: mp 106.5-107.5 °C; 1H NMR (300 MHz, CDCl3) δ 7.30 (br s, 1H),
4.45-4.36 (m, 1H), 3.46 (dd, 1H, J ) 10.1, 5.9 Hz), 3.11 (dd, 1H, J )
9.9, 3.7 Hz), 2.42 (dd, 1H, J ) 16.9, 6.6 Hz), 2.13 (dd, 1H, J ) 16.9, 4.4
Hz); 13C NMR (75 MHz, CDCl3) δ 176.7, 67.4, 51.5, -0.3; MS (DCI/
NH3): m/z 174 [M + H]+, 191 [M+NH4]+, 208 [M + NH3‚NH4]+, 347
[2M + H]+; FAB-HRMS: Calcd m/z for [M + H]+ C7H16NO2Si: 174.0950,
found: 174.0948; Anal. Calcd for C7H15NO2Si: C, 48.52; H, 8.72; N, 8.08;
found: C, 48.51; H, 8.55; N, 8.07.
(6) Pellegata, R.; Pinza, M.; Pifferi, G. Synthesis 1978, 614.
416
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10.1021/op025532+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/17/2002

proceeded, the product (()-N-Boc-4-hydroxy-2-pyrrolidinone
6 crystallized from the reaction mixture. Heptane was
charged to the suspension to maximize product recovery. This
one-pot three-step sequence provided 6 in 97% overall yield
in the laboratory and in 89% yield on 15-kg scale in the
pilot plant. After our work was completed, a communica-
tion10 describing the synthesis of (S)-(+)-N-Boc-4-hydroxy-
2-pyrrolidinone from N-Boc-2-pyrrolidinone by resting cells
of Sphingomonas sp. HNX-200 was published. This bio-
catalytic process can generate the desired product in 46%
yield and 92% ee.
The stable crystalline 6 was a convenient intermediate to
stockpile for ready access to TBSOP. To convert 6 to
TBSOP, the intermediate was dissolved in THF and the
dehydration was accomplished by treatment with methane-
sulfonyl chloride and triethylamine to give the N-Boc-∆3-
pyrrolidinone 7. After the reaction was complete shown by
HPLC analysis of starting material of less than 1%, it was
diluted with ethyl acetate (to precipitate byproduct triethyl-
ammonium hydrochloride) and filtered. The filtrate was
washed with brine solution and dried by azeotropic distil-
lation with heptane. To the mixture of 7 and heptane was
added triethylamine and a filter agent.11 The mixture was
chilled to 0 °C and treated with tert-butyldimethylsilyl
trifluoromethanesulfonate. The triethylammonium trifluo-
romethanesulfonate formed as a byproduct was absorbed onto
the filter agent as the reaction progressed. At the end of
reaction, the darkened filter agent was removed by filtration.
All other reaction byproducts were volatile and were removed
by concentration of the filtrate. For use in our process, the
residue was reconstituted in heptane and held for next step.
The HPLC assayed yield of TBSOP was 95-98%.
relative to tetramethylsilane (TMS) as an internal standard.
Melting points were determined on a Thomas-Hoover
capillary melting point apparatus and were uncorrected.
Elemental analyses were performed by Robertson Microlit
Laboratories. Column chromatography was carried out on
silica gel 60 (230-400 mesh). Thin-layer chromatography
(TLC) was performed using 250 mm silica gel 60 glass-
backed plates with F254 as indicator. Visualization of TLC
was done by UV light, KMnO4 or phosphomolybdic acid
spray reagent.
Preparation of (()-N-Boc-4-hydroxy-2-pyrrolidinone
(6). To a jacketed reactor were charged (()-4-amino-3-
hydroxy-n-butyric acid 1 (10.0 kg), pyridine (48.9 kg),
1,1,1,3,3,3-hexamethyldisilazane (21.9 kg) and xylenes (86.4
kg). The reaction mixture was stirred and heated to reflux
(118 °C) for 14 h (jacket temperature was set at 140 °C).
In-process analysis showed that the reaction was complete.
The reaction mixture was cooled and volatile solvents were
distilled under reduced pressure. The reaction mixture was
cooled to e+10 °C and a solution of DMAP (0.494 kg) in
isopropyl acetate (18.3 kg) was charged to the reaction
mixture, followed by another solution of di-tert-butyl dicar-
bonate (21.5 kg) in isopropyl acetate (27.9 kg). The reaction
mixture was stirred for 30 min at +15 °C and for 17 h at
+20 °C. When the in-process sample showed that the
reaction was complete, triethylamine trihydrofluoride (5.9
kg) was charged to the reaction mixture over a period of 15
min. The reaction mixture was stirred for 1 h when analysis
showed that the TMS cleavage was complete. The stirring
speed was slowly increased while heptane (111.2 kg) was
charged over a period of 2 h. Reaction mixture was cooled
to 0 °C and stirred for 2.5 h. The product 6 was collected
by filtration and washed with heptane (51 kg) that was first
used to rinse the reactor. 6 was initially dried in the filter
pot with nitrogen for 3 h, and then dried under vacuum at
40 °C for 8 h; yield 15 kg (89% yield), mp 150.4-151.4 °C
dec; 1H NMR (300 MHz, CDCl3) δ 4.50-4.46 (m, 1H), 3.90
(dd, 1H, J ) 12.1, 5.1 Hz), 3.78 (ddd, 1H, J ) 12.4, 2.03,
1.1 Hz), 2.79 (dd, 1H, J ) 17.8, 5.9 Hz), 2.54 (ddd, 1H, J
) 17.8, 2.4, 1.1 Hz), 2.21 (br. s, 1H), 1.53 (s, 9H). 13C NMR
(75 MHz, DMSO-d6) δ 172.4, 149.8, 81.6, 61.9, 55.2, 42.5,
27.7. MS (DCI/NH3): m/z 202 [M+H]+, 219 [M + NH4]+;
FAB-HRMS: Calcd m/z for [M + H]+, 202.1079, found:
202.1079, Anal. Calcd for C9H15NO4: C, 53.72; H, 7.51;
N, 6.96; found: C, 53.84; H, 7.74; N, 7.12.
Advantages of this process are the high overall yield and
the operational efficiency that avoids any chromatographic
purification. There is only one isolation step, and the
intermediate 6 is a stable crystalline solid that can be stored
prior to facile conversion to TBSOP. The process is very
robust and has been demonstrated on different scales.
Experimental Section
General Procedure. Starting materials, reagents, and
solvents were purchased from commercial suppliers and were
1
used without further purification. H NMR spectra were
recorded at 300 or 500 MHz and 13C NMR spectra were
recorded at 75 MHz with chemical shifts (δ ppm) reported
Preparation of N-Boc-2-tert-butyldimethylsiloxypyr-
role (TBSOP). To a 100-L reactor equipped with an addition
funnel, a nitrogen inlet, and a temperature probe was charged
6 (3.20 kg, 15.6 mole). THF (31.3 kg) and triethylamine
(4.425 kg) were added. The reaction mixture was cooled to
0 °C. Methanesulfonyl chloride (2.319 kg) was charged to
the reaction mixture over a period of 2 h while maintaining
the temperature of reaction mixture below 5 °C. The reaction
mixture was stirred at 5 °C for 30 min and at ambient
temperature for 2 h. Analysis of an in-process sample showed
that the reaction was complete. Ethyl acetate (40 L) was
charged and the reaction mixture was stirred for 30 min.
Triethylammonium chloride was removed by filtration and
(8) (()-N-tert-Butyloxycarbonyl-4-(trimethylsiloxy)-2-pyrrolidinone (5) was
prepared and characterized: mp 65.5-66.5 °C; 1H NMR (300 MHz, CDCl3)
δ 4.40-4.35 (m, 1H), 3.87 (dd, 1H, J ) 11.6, 5.7 Hz), 3.63 (ddd, 1H, J )
11.6, 2.9, 0.9 Hz), 2.72 (dd, 1H, J ) 17.3, 6.3 Hz), 2.46 (ddd, 1H, J )
17.3, 2.9, 0.9 Hz), 1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 172.0, 149.8,
82.7, 63.3, 55.2, 42.9, 27.8, -0.3; MS [ESI (+) ion]: m/z 274 [M + H]+,
291 [M + NH4]+, 296 [M + Na]+, 564 [2M + NH4]+, 564 [2M+ NH4]+,
569 [2M + Na]+; FAB-HRMS: Calcd m/z for [M + H]+ C12H24NO4Si:
274.1475, found: 274.1468; Anal. Calcd for C12H23NO4Si: C, 52.72; H,
8.48; N, 5.12; found: C, 52.45; H, 8.33; N, 5.12.
(9) We do not have quantitative data of triethylamine trihydrofluoride (Et3N‚
3HF) on glass etching, but we did take the precaution of using a stainless
steel reactor rather than a glass-lined reactor for this step of the reaction.
Triethylamine trihydrofluoride (Et3N‚3HF) is a liquid and easy to handle
in operation. Its high concentration of fluoride ion makes the reaction
volume small, which benefits process scale-up.
(10) Chang, D.; Witholt, B.; Li, Z. Org. Lett. 2000, 2, 3949.
(11) A filter agent such as Celite or diatomaceous earth is suitable.
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washed with isopropyl acetate (2 × 13.3 L). The filtrate was
washed with 15 wt % NaCl solution (2 × 13 L). The
combined aqueous washes (15 wt % NaCl) were back-
extracted with the isopropyl acetate (26.6 L) obtained from
washes of the triethylammonium chloride cake. All organic
layers and extracts containing 7 were combined and con-
centrated to about 20 L. Heptane (20 L) was charged to the
concentrate and distilled under reduced pressure. This process
was repeated four times to remove water, ethyl acetate, and
isopropyl acetate, and finally a slurry of 7 in heptane (30 L)
was obtained. Dichloromethane (37 L) was charged to the
slurry to dissolve 7, followed by filter agent (3.3 kg), heptane
(25.8 kg), and triethylamine (4.5 kg). The reaction mixture
was cooled to ca. 0 °C. tert-Butyldimethylsilyl trifluo-
romethane-sulfonate (TBSOTf) (4.705 kg) was added over
a period of 1 h while maintaining the internal temperature
below +4 °C. The reaction mixture was stirred at 0 °C for
1 h, when analysis of an in-process sample showed that the
conversion was complete. Methanol (1.0 L) was added to
the reaction mixture over a period of 10 min to quench the
reaction. The reaction mixture was stirred at 0 °C for 20
min, then was concentrated under reduced pressure to about
20 L. Heptane (20 L) was charged to the suspension and
concentrated under reduced pressure to replace dichlo-
romethane. This process was repeated four times and finally
a suspension in heptane (30 L) was obtained. The mixture
was cooled to ca. 0 °C and stirred for 1 h. The solid filter
agent was removed by filtration under nitrogen, and washed
with heptane (20 L). The TBSOP product solution was
distilled to the desired concentration (39.3 wt %) and held
for next step, yield by assay 4.486 kg (95% yield). 1H NMR
(300 MHz, CDCl3) δ 6.69 (dd, 1H, J ) 3.9, 2.1 Hz), 5.90
(t, 1H, J ) 3.7 Hz), 5.23 (dd, 1H, J ) 3.5, 2.1 Hz), 1.57 (s,
9H), 0.99 (s, 9H), 0.22 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 148.2, 143.5, 113.0, 108.0, 92.3, 82.7, 28.0, 25.7, 18.4,
-4.86.
Acknowledgment
The authors thank the Structural Chemistry Department
of Abbott Laboratories for spectroscopic determinations and
Drs. David Barnes, Paul Nichols, and John DeMattei for
useful discussions.
Received for review March 20, 2002.
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