A synthesis of abemaciclib utilizing a Leuckart-Wallach reaction

Article abstract of DOI:10.1016/j.tetlet.2014.12.082

A concise total synthesis of CDK 4/6 inhibitor abemaciclib is described. The synthesis uses a Suzuki coupling, followed by a Hartwig-Buchwald amination to join three of the four subunits. The final step is a reductive amination utilizing Leuckart-Wallach conditions. Key to the Leuckart-Wallach reaction was the addition of trimethyl orthoformate to remove water formed during the reaction, allowing the reaction to go to completion.

Full text of DOI:10.1016/j.tetlet.2014.12.082

Tetrahedron Letters 56 (2015) 949–951
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Tetrahedron Letters
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A synthesis of abemaciclib utilizing a Leuckart–Wallach reaction
⇑
Michael O. Frederick , Douglas P. Kjell
Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise total synthesis of CDK 4/6 inhibitor abemaciclib is described. The synthesis uses a Suzuki
coupling, followed by a Hartwig–Buchwald amination to join three of the four subunits. The final step
is a reductive amination utilizing Leuckart–Wallach conditions. Key to the Leuckart–Wallach reaction
was the addition of trimethyl orthoformate to remove water formed during the reaction, allowing the
reaction to go to completion.
Received 3 December 2014
Revised 12 December 2014
Accepted 14 December 2014
Available online 7 January 2015
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Abemaciclib
Leuckart–Wallach reaction
Reductive amination
Hartwig–Buchwald coupling
Suzuki coupling
Cyclin-dependent kinases play a key role in regulating cell cycle
progression. In many cancers, there is a loss of control in regulating
the cell cycle in response to increased signaling from CDK 4/6. As a
result, there is uncontrolled growth of cancer cells.1 Abemaciclib
(1) is a cell-cycle inhibitor, designed to block the growth of cancer
cells by specifically inhibiting CDK 4 and 6. Abemaciclib has shown
evidence of single-agent activity in patients with advanced non-
small cell lung cancer and breast cancer in a Phase I study. It is also
under investigation as a combination therapy for breast cancer.
Retrosynthetically, we planned to break the molecule in three
places giving commercially available building blocks 2, 3, 4, and
5 (Fig. 1). We envisioned connecting building blocks 2 and 3
through a Suzuki coupling reaction,2 building blocks 3 and 4
through a Buchwald–Hartwig type coupling,3 and building blocks
4 and 5 through a reductive amination.
It is well documented in the literature that the chloride in the 4-
position of dichloro-pyrimidine 2 is generally the most reactive in
palladium mediated reactions,4 so this bond was targeted first
through a Suzuki coupling between boronic ester 3 and pyrimidine
2 (Scheme 1). Use of PdCl2(PPh3)2 with Na2CO3 in DME at 80 °C
provided the desired biaryl compound 6 in 66% yield.5 To form
the carbon–nitrogen bond, we explored a Buchwald–Hartwig ami-
nation. The choice of solvent was important for this reaction due to
solubility limitations. While alcohols provided adequate solubility,
unhindered alcohols such as MeOH and EtOH displaced the
chloride and provided the corresponding ethers as unwanted by-
products. Use of the more hindered tAmylOH fortunately allowed
the reaction to work well without observing any of the undesired
tAmyl ether by-product. Ligand choice was also important, as
PPh3 was not active enough to provide full conversion and gener-
ally resulted in stalled reactions. We, fortunately, found DPEPhos
was a sufficiently active catalyst,6 to provide the desired product
7 in 99% yield.7
The final reaction in the synthesis was a reductive amination
between aldehyde 7 and N-ethylpiperazine 5. Initially, we explored
NaBH(OAc)3 as the reductant (Table 1, entry 1).8 Although com-
plete conversion was observed, product (1) was obtained as a
97:3 mixture with the corresponding alcohol (8) and could ulti-
mately not be further purified through crystallization. Typical
hydrogenative conditions (hetero- and homogeneous catalysts
with H2)9 caused similar problems with reduction to the alcohol
(8, results not listed). These setbacks led to the exploration of Leu-
ckart–Wallach conditions,10,11 utilizing formic acid as the reducing
agent without the use of a catalyst. Given the presumed reaction
mechanism,12 we theorized that reduction of the alcohol would
not be observed. This was indeed the case, and running the reac-
tion with 2 equiv of formic acid and 1.5 equiv of N-ethylpiperazine
5 gave 73% conversion, with no alcohol (8) observed and the
remainder being starting aldehyde 7 (entry 2). Increasing equiva-
lents of both formic acid and N-ethylpiperazine (5) improved con-
version (entries 3–5), but ultimately the reaction stalled. We
hypothesized that water formed during the course of the reaction
was ultimately causing the reaction to stall, so we explored ways
to remove the water in situ.13 Trimethyl orthoformate is known
to facilitate the removal of water when added either as a solvent,14
or co-solvent15 driving the formation of an imine to completion,
but to our knowledge, this has not been explored with one-step
⇑
Corresponding author. Tel.: +1 317 655 9116.
E-mail address: frederickmo@lilly.com (M.O. Frederick).
http://dx.doi.org/10.1016/j.tetlet.2014.12.082
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

950
M. O. Frederick, D. P. Kjell / Tetrahedron Letters 56 (2015) 949–951
F
reductive aminations, or more specifically with the Leuckart–
N
N
Wallach reaction. Fortunately, adding 2 equiv of trimethyl ortho-
formate facilitated driving the reaction to completion affording
an isolated yield of 74% for abemaciclib (1).16
F
N
N
In conclusion, we have developed a short, 3-step synthesis of
drug candidate abemaciclib (1) from commercially available
starting materials. Key to the synthesis was a Leuckart–Wallach
reductive amination to avoid reduction of the aldehyde, which
relied on trimethyl orthoformate to trap the water generated and
allowed the reaction to go to completion.
HN
N
N
N
1
Abemaciclib ( )
F
F
N
N
Cl
Acknowledgments
O
B
O
N
N
Cl
2
The authors would like to thank Kenji Yagi, Naota Yokoyama,
and Masaharu Matsushita at Takasago for helpful discussions and
suggestions during the development of the Leuckart–Wallach
reductive amination.
3
H2N
N
HN
H
N
O
4
5
References and notes
Figure 1.
1. Malumbres, M.; Harlow, E.; Hunt, T.; Hunter, T.; Lahti, J. M.; Manning, G.;
Morgan, D. O.; Tsai, L.-H.; Wolgemuth, D. J. Nat. Cell Biol. 2009, 11, 1275.
2. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437; (b)
Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
3. (a) Buchwald, S. et al Acc. Chem. Res. 1998, 31, 805; (b) Hartwig, J. Acc. Chem.
Res. 1998, 31, 852.
F
Cl
N
N
4. For recent examples utilizing the pyrimidine selectivity see: (a) Mollard, A.;
Warner, S. L.; Call, L. T.; Wade, M. L.; Bearss, J. J.; Verma, A.; Sharma, S.;
Vankayalapati, H.; Bearss, D. J. ACS Med. Chem. Lett. 2011, 2, 907; (b) William, A.
D. et al J. Med. Chem. 2011, 54, 4638.
5. Procedure for the synthesis of biaryl compound 6: To a 250 mL 3-neck round
bottom flask equipped with a N2 inlet, overhead stirrer, reflux condenser and
temperature probe was charged 5-fluoro-2,4-dichloropyrimidine (2, 5.17 g,
31.0 mmol, 1.4 equiv), Na2CO3 (5.86 g, 55.3 mmol, 2.5 equiv), water (9 mL), and
DME (45 mL). The solution was degassed by sparging N2 subsurface for 30 min.
F
F
N
N
Cl
F
N
N
2
O
PdCl2(PPh3)2, DME,
Na2CO3, 80 °C
B
O
N
N
Cl
6
3
F
N
NH2
N
F
After subsurface sparging, PdCl2(PPh3)2 (46.6 mg, 66 lmol, 0.03 equiv) was
H
N
added in one portion. The resulting solution was heated to 80 °C. In a separate
100 mL round bottom flask was charged boronic ester 3 (7.04 g, 22.1 mmol,
1.0 equiv) and DME (40 mL). The resulting solution was added to the heated
solution by syringe pump over the course of 1.5 h. After all of boronic ester 3
was added, the reaction solution was stirred at 80 °C for an additional 4 h, at
which time the reaction was complete as judged by HPLC analysis. The reaction
mixture was then cooled to ambient temperature and diluted with ice cold
water (300 mL) and stirred for 25 min. The resulting slurry was collected by
filtration and the resulting wetcake was slurried in IPA (105 mL) and heated to
80 °C for 3.5 h. The heated slurry was then allowed to cool to ambient
temperature over 16 h and the solid was collected by filtration and washed
with IPA (35 mL). The wetcake was dried in a vacuum oven at 45 °C for 18 h to
obtain the desired biaryl compound 6 in 66% yield. Compound 6: IR (film)
O
N
N
4
HN
N
PdCl2, DPEPhos
tAmylOH, 100 °C
H
7
O
Scheme 1.
Table 1
m
max = 3413, 2972, 2940, 2892, 1567, 1507, 1401, 1388, 1348, 1210 cmÀ1 1H
;
F
F
NMR (500 MHz, CDCl3): d = 8.50 (d, J = 3.4 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.77
(d, J = 11.7 Hz, 1H), 4.74 (septet, J = 7.0 Hz, 1H), 2.69 (s, 3H), 1.69 (d, J = 7.0 Hz, 6
H) ppm; 13C NMR (125 MHz, CDCl3): d = 155.3, 154.8, 154.2, 153.9, 153.2,
148.4, 136.6, 134.7, 125.5, 108.8, 108.2, 48.7, 21.5, 15.2 ppm; HR-MS [ESI]:
Calcd for C15H14N4ClF2 [M+H+]: 323.0870, found 323.0864.
N
N
N
N
F
F
HN
N
5
N
HN
N
N
N
1
+
Conditions a
N
HN
N
6. Wolfe, J. P. Bis-[2-(diphenylphosphino)phenyl]ether (Dpe-Phos); e-EROS
Encyclopedia of Reagents for Organic Synthesis, 2011.
H
7. Procedure for the synthesis of aldehyde 7: To a 250 mL 3-neck round bottom
flask equipped with a N2 inlet, overhead stirrer and temperature probe was
charged aminoaldehyde 4 (6.13 g, 50.2 mmol, 1.25 equiv), biaryl compound 6
(12.96 g, 40.2 mmol, 1.0 equiv), PdCl2 (214 mg, 1.21 mmol, 0.03 equiv), K2CO3
(5.6 g, 40.2 mmol, 1.0 equiv), and 2-methyl-2-butanol (130 mL). The resulting
slurry was heated to 100 °C for 18 h at which point the reaction was deemed
complete by HPLC analysis. The slurry was then cooled to ambient
temperatures and the solid was collected by filtration. The wetcake was
washed with water (30 mL) followed by acetone (30 mL) and then dried in a
vacuum oven at 45 °C for 16 h to afford aldehyde 7 (16.3 g, 40.1 mmol, 99%
7
8
OH
O
Entry
Conditions
Conversion
1:8
Isolated
yield
1
2
3
4
5
6
NaBH(OAc)3 (3 equiv),
5 (2 equiv), DCMb
100
73
97:3
69
Formic acid (2 equiv),
5 (1.5 equiv), ACNc
Formic acid (4 equiv),
5 (1.5 equiv), ACNc
Formic acid (2 equiv),
5 (3 equiv), ACNc
100:0
100:0
100:0
100:0
100:0
N/A
N/A
N/A
N/A
74
yield) as an off-white solid. Compound 7: IR (film)
m
;
max = 3229, 3173, 3041,
86
1973, 1681, 1576, 1421, 1370, 1292, 1222, 1117 cmÀ1
1H NMR (600 MHz, TFA-
d): d = 9.94 (s, 1H), 8.90 (s, 1H), 8.68 (s, 1H), 8.65 (d, J = 9.2 Hz, 1H), 8.42 (s, 1H),
8.07 (d, J = 10.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 5.00 (m, 1H), 2.92 (s, 3H), 1.74
(d, J = 6.7 Hz, 6H) ppm; 13C NMR (150 MHz, TFA-d): d = 192.6, 155.8, 155.7,
155.3, 155.0, 154.3, 151.9, 149.0, 145.5, 144.2, 135.4, 133.2, 128.9, 124.4, 119.4,
115.8, 114.1, 55.4, 21.9, 13.7 ppm; HR-MS [ESI]: Calcd for C21H18F2N6OH+
[M+H+]: 409.1583, found 409.1579.
92
Formic acid (4 equiv),
95
5 (3 equiv), ACNc
Formic acid (4 equiv),
5 (2 equiv), ACNc,d
100
8. (a) Abdel-Magid, A. F.; Mehrman, S. J. Org. Process Res. Dev. 2006, 10, 971; (b)
Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J.
Org. Chem. 1996, 61, 3849; (c) Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proced. Int.
1985, 17, 317; (d) Gribble, G. W. Chem. Soc. Rev. 1998, 27, 395.
9. (a) Mallat, T.; Baiker, A. In Handbook of Heterogeneous Catalysis; VCH:
Weinheim, 1997; Vol. 5,; pp 2334–2348; (b) Klyuev, M V.; Khidekel, M. L.
a Reactions run on 0.1 mmol scale except entry 6 (1.0 mmol).
b
At 22 °C.
At 80 °C.
c
d
2 equiv trimethyl orthoformate added.

M. O. Frederick, D. P. Kjell / Tetrahedron Letters 56 (2015) 949–951
951
Russ. Chem. Rev. 1980, 49, 14; (c) Rylander, P. A. Catalytic Hydrogenation over
Platinum Metals; Academic Press: New York, 1967; pp 291–303; (d) Frederick,
M. O.; Frank, S. A.; Vicenzi, J. T.; LeTourneau, M. E.; Berglund, K. D.; Edward, A.
W.; Alt, C. A. Org. Process Res. Dev. 2014, 18, 546.
1.0 equiv), N-ethylpiperazine (0.31 mL, 2.45 mmol, 2.0 equiv), ACN (5 mL),
trimethyl orthoformate (0.27 mL, 2.45 mmol, 2.0 equiv), and formic acid
(0.187 mL, 4.9 mmol, 4.0 equiv). The reaction vessel was sealed and the
stirring mixture was heated to 80 °C for 16 h. The resulting slurry was cooled to
ambient temperatures and the solid was collected by filtration. The wetcake
was then washed with ACN (5 mL) and then dried in the vacuum oven at 45 °C
for 16 h to afford abemaciclib 1 (456 mg, 0.90 mmol, 74% yield) as an off-white
10. (a) Leuckart, R. Ber. Dtsch. Chem. Ges. 1886, 18, 2341; (b) Leuckart, R.; Bach, E.
Ber. Dtsch. Chem. Ges. 1886, 19, 2128; (c) Wallach, O. Ber. Dtsch. Chem. Ges.
1891, 24, 3992.
11. Lee, S.-C.; Park, S. B. Chem. Commun. 2007, 3714.
solid. Compound 1: IR (film)
m
max = 3232, 3167, 3089, 3030, 2970, 2936, 2810,
12. (a) Crossley, F. S.; Moore, M. L. J. Org. Chem. 1944, 9, 529; (b) Alexander, E. R.;
Wildman, R. B. J. Am. Chem. Soc. 1948, 70, 1187; (c) Webers, V. J.; Bruce, W. F. J.
Am. Chem. Soc. 1948, 70, 1422; (d) Pollard, C. B.; Young, D. C. J. Org. Chem. 1951,
16, 661.
13. Staple, E.; Wagner, E. C. J. Org. Chem. 1949, 14, 559.
14. Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A. Tetrahedron Lett.
1995, 36, 2937.
1584, 1533, 1477, 1434, 1398, 1291 cmÀ1
;
1H NMR (400 MHz, CDCl3): d = 9.05
(s, 1H), 8.47 (d, J = 6.0 Hz, 1H), 8.38 (d, J = 12.0 Hz, 1H), 8.30 (d, J = 3.0 Hz, 1H),
8.16 (d, J = 1.5 Hz, 1H), 7.75 (dd, J = 12.0, 1.5 Hz, 1H), 7.66 (dd, J = 12.0, 3.0 Hz,
1H), 4.70 (septet, J = 6.0 Hz, 1H), 3.47 (s, 2H), 2.65 (s, 3H), 2.48 (br m, 8H), 2.39
(q, J = 12.0 Hz, 2H), 1.68 (d, J = 6.0 Hz, 6H), 1.05 (t, J = 12.0 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3): d = 155.5, 153.7, 153.5, 152.4, 151.5, 151.1, 148.9,
147.4, 139.2, 136.6, 134.2, 127.7, 127.3, 111.6, 108.9, 108.3, 60.0, 53.1, 52.9,
52.5, 48.8, 21.6, 15.2, 12.2 ppm; HR-MS [ESI]: Calcd for C27H32F2N8H+ [M+H+]:
507.2791, found 507.2789.
15. (a) Peters, J.-U.; Blechart, S. Synlett 1997, 348; (b) Park, K.-H.; Kurth, M. J.
Tetrahedron Lett. 1999, 40, 5841.
16. Procedure for the synthesis of abemaciclib 1: To a 20 mL reaction vessel
equipped with
a stir bar was charged aldehyde 7 (500 mg, 1.22 mmol,