Process development and pilot-plant synthesis of (S)-tert-butyl 1-oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate: Studies on the scale-up of Kulinkovich-Szymoniak cyclopropanation

Article abstract of DOI:10.1021/op300059b

A practical and scalable synthesis of (S)-tert-butyl 1-oxo-1-(1-(pyridin-2- yl)cyclopropylamino)propan-2-ylcarbamate, an intermediate in the manufacture of a lymphocyte function-associated antigen 1 inhibitor, is described. The titled compound is prepared via an efficient one-pot, two-step telescoped sequence starting from readily available materials. A modified Kulinkovich-Szymoniak cyclopropanation of a nitrile followed by in situ amide formation with an activated carboxylic acid derivative afforded the target product in about 50% overall isolated yield and >97% purity.

Full text of DOI:10.1021/op300059b

Communication
pubs.acs.org/OPRD
Process Development and Pilot-Plant Synthesis of (S)-tert-Butyl 1-
Oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate:
Studies on the Scale-Up of Kulinkovich−Szymoniak
Cyclopropanation
Wenjie Li,* Joe J. Gao, Jon C. Lorenz, Jinghua Xu, Joe Johnson, Shengli Ma, Heewon Lee, Nelu Grinberg,
Carl A. Busacca, Bruce Lu, and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut
06877, United States
S
* Supporting Information
Scheme 1. Retrosynthesis of 1
ABSTRACT: A practical and scalable synthesis of (S)-
tert-butyl 1-oxo-1-(1-(pyridin-2-yl)cyclopropylamino)-
propan-2-ylcarbamate, an intermediate in the manufacture
of a lymphocyte function-associated antigen 1 inhibitor, is
described. The titled compound is prepared via an efficient
one-pot, two-step telescoped sequence starting from
readily available materials. A modified Kulinkovich−
Szymoniak cyclopropanation of a nitrile followed by in
situ amide formation with an activated carboxylic acid
derivative afforded the target product in about 50% overall
isolated yield and >97% purity.
with 2 equiv of ethylmagnesium bromide in the presence of 1
equiv of Ti(OPri)4. The reaction proceeded to give the desired
cyclopropylamine in a modest 55% yield, consistent with the
INTRODUCTION
reported results. The major byproduct of this reaction was
identified as pyridyl ethyl ketone (8), and its formation can be
explained in the mechanism of Kulinkovich−Szymoniak
reaction. As outlined in Scheme 2, reaction between ethyl
■
Recently our development program required a large-scale
synthesis of cyclopropylaminopyridine-(L)-alanine dipeptide
(1), a key intermediate for lymphocyte function-associated
antigen (LFA-1) antagonist as a potential treatment of immune
disorders. Although the synthetic route is relatively straightfor-
ward, extensive development and optimization efforts were
required to implement a practical and scalable process for the
multikilogram production of this seemingly simple molecule.
Our strategy involved a modified protocol of Kulinkovich−
Szymoniak cyclopropanation of 2-cyanopyridine to afford 2-
cyclopropylaminopyridine (2). The reaction mixture of the
cyclopropanation was directly subjected to an amide coupling
with activated Boc-(L)-alanine without purification or isolation.
This one-pot, two-step sequence enabled the multikilogram
preparation of the dipeptide (1) in pilot-plant without column
purification (Scheme 1).
Scheme 2. Reaction mechanism for the formation of 2 and 8
RESULTS AND DISCUSSION
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Szymoniak and Bertus have reported that treatment of nitriles
with ethyl Grignard reagents and titanium tetraisopropoxide
followed by a Lewis acid (such as BF3·OEt2) afforded
cyclopropylamines.1−4 This is a variation of the commonly
known Kulinkovich reaction,5−13 which involves the synthesis
of cyclopropanols from esters using ethylmagnesium bromide
and titanium tetraisopropoxide. Following the reaction
conditions described by Szymoniak, our synthesis started
from readily available 2-cyanopyridine, which was treated
magnesium bromide and titanium tetraisopropoxide gives
titanacyclopropane 5, which undergoes addition to the nitrile
group to form azatitanacyclopentane 6 as intermediate.
Contraction of 6 leads to the desired cyclopropylamine (2).
If the contraction of 6 is slow, ethyl ketone 8 could be obtained
Received: March 8, 2012
Published: April 18, 2012
© 2012 American Chemical Society
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Communication
Scheme 3. Addition of the diamine ligand 9 to improve the yield of 2
after workup. Another possibility for the formation of 8 is that
ethyl Grignard reagent undergoes direct addition to the nitrile
to give 7 instead of forming the titanacyclopropane species 5.
It has been discovered by this department that the organic
ligand bis[2-(N,N-dimethylaminoethyl)]ether (9) can modu-
late the reactivity of the organomagnesium reagents.14−16
Therefore, it was envisioned that bis[2-(N,N-
dimethylaminoethyl)]ether (9) could form a complex with
ethyl Grignard reagent and moderate its reactivity, thereby
suppressing the addition of ethyl Grignard reagent to the nitrile
group. Indeed, addition of this ligand to the reaction mixture
gave a cleaner reaction profile with less formation of 817 (see
Scheme 3). Due to the decreased reactivity, the reaction needs
to be run at high temperature (over 60 °C). As a result, the
contraction of intermediate 6 is also accelerated, and therefore
less 8 is formed.18
2-cyanopyridine (4) in the reaction mixture remained at low
level because it was quickly consumed by the reagents while
being added.19 As a result, the reaction gave a much cleaner
profile as byproduct formation was minimized. The yield of the
product 2 was increased to 70−75% by HPLC assay.
Although the yield for cyclopropanation had been signifi-
cantly improved, serious challenges remained for running the
reaction at large scale. The reaction produced a large amount of
titanium and magnesium salt, and their removal was tedious
and difficult. More importantly, the isolation and purification of
product cyclopropylamine (2) was problematic because it had
high solubility in water. Any extractive workup, which is often
needed to remove inorganic salt, would result in significant loss
of product in the aqueous layer. One way to address this issue is
to derivatize the amine (2), making it less soluble in aqueous
media. We soon realized that the most convenient derivative for
the amine was the desired product 1. The ideal condition would
be the one that allowed the amide to be formed in situ after the
cyclopropanation without isolating amine 2. To this end we
chose to use carbonyldiimidazole (CDI) as the activating agent,
and developed a one-pot procedure for the in situ formation of
the amide. As illustrated in Scheme 4, after the cyclo-
propanation reaction was complete, the right amount of acetic
acid (7.88 equiv) and water (1 vol) were added to the reaction
mixture to adjust the pH between 6 and 7. In a separate reactor,
N-Boc-alanine imidazole derivative (10) was prepared by
mixing N-Boc-alanine (3) with CDI. The solution containing
10 was then transferred to the reaction mixture of 2. The
reaction proceeded smoothly to provide the desired coupling
product 1. At this point, most of the inorganic salts (titanium
and magnesium) were precipitated out of the reaction mixture
and could be easily filtered off. The filtrate was washed with
sodium potassium tartrate (Rochelle salt) aqueous solution to
remove residual inorganic salt. Finally, the product was isolated
by crystallization from methyl tert-butyl ether and heptane. The
overall yield for the entire sequence was 60−65% by solution
assay (5−8% lost to filtrate), and the isolated yield was
consistently at 48−50% at multikilo scale. The process was
streamlined and scaled up smoothly in pilot plant, and the
product 1 was isolated in high quality.
Our initial procedure for the cyclopropanation involved
addition of ethyl Grignard reagent to the mixture of 2-
cyanopyridine, Ti(OPri)4, and diamine ligand (9) in 2-methyl
THF. Although the reaction profiles were cleaner than those
without the diamine ligand, several low-level byproducts were
detected (Figure 1). LC/MS analysis revealed they were
Figure 1. Byproducts detected in the cyclopropanation.
dimeric species, possibly due to further reaction between the
product (2) and starting material (4).
We rationalized that in order to prevent the formation of
these dimeric byproducts, we needed to reduce the time of
contact between 2-cyanopyridine (4) and the product 2. To
this purpose, a revised procedure was applied in which 2-
cyanopyridine (4) and ethyl Grignard reagent were added
simultaneously at the same rate to a heated solution of diamine
ligand and Ti(OPri)4. Using this process, the concentration of
Scheme 4. One-pot process for the cyclopropanation and amide coupling to synthesize 1
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In summary, we have overcome many challenges related to
scale-up and developed a streamlined, reproducible, and
scalable process for the pilot-plant production of Boc-protected
(S)-2-amino-N-(1-(pyridin-2-yl)cyclopropyl)propanamide. The
Kulinkovich−Szymoniak cyclopropanation reaction was im-
proved by modulating the reactivity of ethyl Grignard reagent
using bis[2-(N,N-dimethylaminoethyl)]ether (9) and simulta-
neous addition of the two reacting agents. The product 2-
cyclopropylaminopyridine (2) was directly subjected to amide
formation without isolation. This one-pot process has been run
successfully in the kilo lab and pilot-plant to produce
multikilogram quantities of the desired compound 1 with
>97% quality. These results provided the required drug
substance to meet the needs of the development program.
(determined by the area % of Boc-(L)-alanine 3 below 0.5%),
it was transferred to reactor 1. The reaction mixture was stirred
at 50 °C for 30 min to 1 h. A sample was taken for HPLC
analysis (method 1). Once reaction reached completion
(determined by the area % of 1-(pyridin-2-yl)-
cyclopropanamine 2 below 5%), the batch was filtered through
a pad of Celite, and the solid cake was rinsed with 2-methyl
THF (68.2 kg). HPLC analysis of the solid cake showed no
product present. The filtrate was transferred to the reactor and
distilled to ∼1/2 volume. An aqueous solution of sodium
potassium tartrate (25 wt %, 152 kg) was charged. The phases
were separated after the mixture was agitated for 15−30 min.
The organic layer was distilled under vacuum. Heptane (80 kg)
was charged, and the batch was concentrated under vacuum.
Heptane (54.6 kg), methyl tert-butyl ether (29.6 kg), and water
(12.8 kg) were charged to the reactor. The mixture was heated
to 60 °C for 30 min and cooled to 20 °C. The solid was
collected by filtration, washed with MTBE/heptane (1:2) and
water, and dried to obtain 11.505 kg of 1 with 97.9% purity
(48.0% isolated yield) and 97.4% ee.20 mp 151.2−151.6 °C; 1H
NMR (400 MHz, CDCl3) δ 1.13 (d, 2H, J = 4 Hz), 1.32 (d,
3H, J = 8 Hz), 1.41 (s, 9H), 1.50 − 1.57 (m, 2H), 4.27 (t, 1H, J
= 8 Hz), 5.63 (d, 1H, J = 8 Hz), 6.94 (t, 1H, J = 8 Hz), 7.27 (d,
1H, J = 8 Hz), 7.44 (t, 1H, J = 8 Hz), 7.65 (s, 1H), 8.36 (d, 1H,
J = 4 Hz); 13C NMR (100 MHz, CDCl3) δ 18.29, 19.12, 28.33,
35.97, 50.17, 79.91, 119.19, 120.49, 135.95, 148.99, 155.76,
160.71, 174.05; HRMS (m/z) [M + H]+ calcd for C16H24N3O3,
306.1812, found, 306.1804.
EXPERIMENTAL SECTION
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General. Bis[2-(N,N-dimethylaminoethyl)]ether and 2-
methyl THF were tested by Karl Fischer for water content
prior to use. The concentration of ethylmagnesium bromide in
THF solution was taken from supplier COA without titration.
HPLC analyses were performed on Hewlett-Packard 1200
system. Method 1 (for reaction monitor and product purity):
Halo C-18 column (4.6 mm × 150 mm, 2.7 μm); elution: 0.1%
HClO4 in H2O with 40 mM NH4PF6/HPLC grade acetonitrile
= 99.5:0.5 up to 0.7 min to 80:20 at 1.3 min to 65:35 at 6 min
to 50:50 at 6.5 min.; flow rate 1.5 mL/min.; 30 °C; UV
detection at 215 nm. Method 2 (for chiral purity): Regiscell
column (4.6 mm × 250 mm, 5 μm); elution: HPLC grade
heptane/ethanol = 97:3 up to 10 min.; flow rate 2.0 mL/min.;
25 °C; UV detection at 254 nm.
ASSOCIATED CONTENT
■
S
GC analyses were performed on a HP 6890 GC or equivalent
equipped with MSD detector. J&W 122-0731 DB1701 column
(30 m × 0.25 mm, 0.15 μm); inlet mode: split; split ratio =
75:1; temperature 150 °C; carrier gas: helium; 1.3 mL/min
constant flow; syringe: 10 μL; injection volume: 1.0 μL;
temperature program: 100 to 270 °C at a rate of 25 °C/min,
hold at 270 °C for 4.0 min; run time: 10.8 min.
* Supporting Information
NMR spectra of compound 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*wenjie.li@boehringer-ingelheim.com
Pilot-Plant Process for the One-Pot Synthesis of (S)-
tert-Butyl 1-Oxo-1-(1-(pyridin-2-yl)cyclopropylamino)-
propan-2-ylcarbamate (1). Part 1. 1-(Pyridin-2-yl)-
cyclopropanamine (2). To a 400-L reactor (Reactor 1) was
charged titanium(IV) isopropoxide (26.48 kg, 93.17 mol),
bis[2-(N,N-dimethylamino)ethyl]ether (27.76 kg, 173.22 mol,
Kf = 1000 ppm), and 2-methyl THF (41 kg, Kf = 147 ppm).
The solution was heated to 50 °C. Ethylmagnesium bromide
(1.0 M in THF, 174.56 kg, 172.89 mol) and 2-cyanopyridine
(8.0 kg, 76.84 mol) in 2-methyl-THF (13.76 kg) solution were
charged simultaneously over 45−60 min (the batch temper-
ature rose to 66 °C and started refluxing). The batch was aged
at 60 °C for 30 min to 1 h. A sample was taken for HPLC
analysis (method 1). Once reaction reached completion
(determined by the area % of 2-cyanopyridine 4 below 2%),
it was cooled to 25 °C. Acetic acid (36.32 kg, 605.52 mol) was
charged slowly (the batch temperature rise to 45 °C, pH
between 6 and 7 after addition), followed by water (7.9 kg,
440.32 mol) to quench the reaction.
Notes
The authors declare no competing financial interest.
REFERENCES
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(13) Wolan, A.; Six, Y. Tetrahedron 2010, 66, 15−61.
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Part 2. (S)-tert-Butyl 1-Oxo-1-(1-(pyridin-2-yl)-
cyclopropylamino)propan-2-ylcarbamate (1). To reactor 2
was charged 1,1′-carbonyldiimidazole (12.48 kg, 76.84 mol) and
2-methyl THF (6.8 kg). A solution of Boc-(L)-alanine (14.56
kg, 76.84 mol) in 2-methyl THF (34.1 kg) was charged slowly.
The solution was stirred at 25 °C for 30 min. A sample was
taken for GC analysis. Once completion was reached
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(16) Wang, X.-J.; Xu, Y.; Zhang, L.; Krishnamurthy, D.; Senanayake,
C. H. Org. Lett. 2006, 8, 3141−3144.
(17) Other diamine ligands (such as TMEDA) were also tried and
found to be less effective than 9.
(18) It was found that raising temperature without adding ligand 9
did not improve the reaction yield.
(19) A control experiment was conducted without the diamine ligand
9, and it indicated that the presence of the ligand 9 was beneficial even
with the simultaneous addition protocol.
(20) The optical purity of 1 exceeded the specifications at this point.
If higher ee % is desired, the compound can be slurried in MTBE/
heptane (1:1, 10× volume) at rt for 1 h. After filtration, the chiral
purity of the isolated material is 99.5% with 2% loss in the filtrate.
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