A convergent preparation of the CHK1 inhibitor MK-8776 (SCH 900776)

Article abstract of DOI:10.1016/j.tetlet.2016.04.102

This Letter describes the development of a convergent, efficient route to the CHK1 inhibitor MK-8776. This synthetic approach relies upon the cyclization of a bispyrazole adduct 10 with a optically pure β-keto nitrile 9 to construct the pyrazolo[1,5-a]pyrimidine scaffold in a single step.

Full text of DOI:10.1016/j.tetlet.2016.04.102

Tetrahedron Letters 57 (2016) 2601–2603
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convergent preparation of the CHK1 inhibitor MK-8776
(
SCH 900776)
⇑
⇑
Marc A. Labroli , Michael P. Dwyer , Cory Poker, Kerry M. Keertikar, Randall Rossman, Timothy J. Guzi
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the development of a convergent, efficient route to the CHK1 inhibitor MK-8776.
This synthetic approach relies upon the cyclization of a bispyrazole adduct 10 with a optically pure b-keto
nitrile 9 to construct the pyrazolo[1,5-a]pyrimidine scaffold in a single step.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 31 March 2016
Revised 19 April 2016
Accepted 27 April 2016
Available online 3 May 2016
Keywords:
Kinase
CHK1
MK-8776
Serine/threonine kinase
Oncology
Checkpoint kinase 1 (CHK1) is a serine/threonine kinase that
controls the cellular response to DNA damage to arrest cells at var-
ious cell-cycle checkpoints (G1, S, G2) in order to initiate the DNA
in the presence of 1-methylpyrazole boronate followed by global
deprotection with TFA/H O afforded intermediate 4.
2
7
a,b
Intermediate 4 was subjected to chiral separation using a
preparative Chiralcel AD column to afford the individual enan-
tiomers, 5 and 6, which required several recycle operations to
afford the optically pure materials (Scheme 2). The separate enan-
tiomers (5 and 6) were then treated with NBS in acetonitrile to
afford the final adducts MK-8776 and its enantiomer 7 in modest
yield.
While the above-mentioned route described in Schemes 1 and 2
could provide gram quantities of MK-8776, there were several key
limitations to this preparation that needed to be addressed. While
this route provided the desired synthetic flexibility to develop
broad SAR in the series, the overall synthetic efficiency of this
sequence toward MK-8776 was poor due to late stage chiral sepa-
ration. Moreover, the chiral separation of racemate 4 was quite
challenging as the column loading was limited by poor solubility
and a tight separation required multiple HPLC runs (recycle
operations) to obtain material of sufficient optical purity (>95%).
Secondly, we wanted to shorten the synthetic sequence by
eliminating the protection/deprotection chemistry with the
expensive SEMCl reagent. Finally, the bromination step on the fully
deprotected materials 5 and 6 proceeded in somewhat variable
1
repair process. Inhibition of CHK1 abrogates cell-cycle arrest
resulting in genomic instability and ultimately progression into
mitosis and cell death.2 Owing to the therapeutic value of a
CHK1 inhibitor as a chemopotentiator, it has been an attractive tar-
get in the oncology field.3 A number of comprehensive reviews
have recently been published which review the emerging CHK1
small-molecule chemotypes.5
,4
The recent efforts at Merck in this area have yielded MK-8776
(
SCH 900776) which demonstrated a preclinical profile supportive
6
of clinical advancement (Fig. 1). In an effort to support additional
profiling of this compound, we required a more robust, efficient
preparation than the original medicinal chemistry route shown
in Schemes 1 and 2.
The original chemistry route toward MK-8776 began with the
cyclization of b-keto ester 1 with 3-aminopyrazole followed by
subsequent chlorination and amination to afford piperidine 2
7
a,b
shown in Scheme 1.
Protection of the resultant 7-amino group
followed by introduction of the C3 iodide via NIS treatment
afforded intermediate 3. Treatment of 3 under Suzuki conditions
yields under
a variety of conditions. Due to these serious
⇑
Corresponding authors. Tel.: +1 215 652 1197 (M.A.L.), +1 732 594 1733
M.P.D.).
E-mail addresses: marc.labroli@merck.com (M.A. Labroli), michael.dwyer@
limitations and the need to generate enough material to support
the preclinical assessment of this candidate, several alternative
preparations were explored.
(
merck.com (M.P. Dwyer).
http://dx.doi.org/10.1016/j.tetlet.2016.04.102
0
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2
602
M. A. Labroli et al. / Tetrahedron Letters 57 (2016) 2601–2603
H
N
N
H
N
N
Boc
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
N
Br
NH
2
NH
2
NH
2
MK-8776
8
Figure 1. Structure of CHK1 inhibitor MK-8776 (SCH 900776).
N
Boc
N
2
H N
Boc
N
O
+
HN
N
Boc
CN
N
N
9
10
d,e
a, b, c
OMe
N
N
Figure 2. Retrosynthetic approach toward MK-8776 using the optically pure b-keto
nitrile 9.
1
NH
2
O
O
2
Boc
N
H
N
N
N
I
PMB
N
N
f,g
H
N
Br
N
Br
2
PMB
N
N
a
b
N
N
N
N
N
H
N
N(SEM)
2
NH2
PMB
3
4
11
1
2
Scheme 1. Reagents and conditions: (a) 3-aminopyrazole, PhCH
N-dimethylaniline, 71%; (c) NH , 2-propanol, H
CN, 92%; (f) 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
3
, 75%; (b) POCl
3
, N,
N
N
N
N
3
2
O, 98%; (d) SEMCl, DIPEA, CH
2
Cl
2
,
7
6%; (e) NIS, CH
-yl)-1H-pyrazole, PdCl
3
(PMB)
2
N
2
H N
c
2
2
dppf, K
3
PO
4
, DME, H
2
O, 81%; (g) HCl, EtOH, 90%.
N
N
N
N
H
PMB
1
0
1
3
H
N
N
Scheme 3. Reagents and conditions: (a) PMBCl, DMF, 75%; (b) 1-methyl-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole, Pd(Ph P) , 69%; (c) TFA, CH Cl ,
3 4 2 2
63%.
H
N
N
H
N
N
N
N
N
N
Chiralcel AD
N
N
+
N
N
N
N
N
N
NH
2
NH
5
2
NH2
6
4
N
N
N
a
b
N
N
N
a
a
O
1
4
H
CN
1
5
16
H
N
N
N
H
N
N
N
N
N
N
N
N
c
N
d
N
2
H N
N
N
N
Br
Br
NH
2
OHC
HN
N
NH
2
CN
MK-8776
7
1
0
1
7
Scheme 2. Reagents and conditions: (a) NBS, CH
3
CN, 65–75%.
Scheme 4. Reagents and conditions: (a) POCl
3
, DMF, 50%; (b) t-BuOK, TosMIC, DME,
NH
ꢀHCl, EtOH, 90%.
65%; (c) ethyl formate, t-BuOK, DME, 82%; (d) NH
2
2
We turned our attention toward an alternative approach that
we had previously employed to assemble the pyrazolo[1,5-a]
The synthesis of the bispyrazole adduct 10 using a second
7
b
7b
pyrimidine cores albeit in racemic form shown in Figure 2. We
envisioned that MK-8776 could be derived from Boc adduct 8 via
a bromination/deprotection sequence. Compound 8 in turn could
be derived from the cyclocondensation of optically pure b-keto
generation approach is shown in Scheme 4. Formylation of
N-methyl-1H-pyrazole 14 under Vilsmeier–Haack conditions
afforded aldehyde 15 which could be treated with tosyl methyl iso-
8
cyanide (TosMIC) in the presence of base to afford nitrile 16.
0
0
nitrile 9 with a 3-amino-1-methyl-1H-1 H-4,4 -bispyrazole 10.
Our initial attempts to prepare the bispyrazole adduct 10 are
shown in Scheme 3. This route involved the tris-p-methoxybenzyl
protection of 4-bromo-1H-pyrazol-3-amine 11 to provide
compound 12. Palladium mediated coupling of 12 with
Formylation of 16 was achieved with ethyl formate in the presence
of potassium tert-butoxide to afford compound 17 followed by
cyclization with hydrazine hydrochloride in EtOH afforded the
desired bispyrazole fragment 10. This provided a more atom eco-
nomical and cost-effective process for preparing sufficient
amounts of bispyrazole 10 to investigate the subsequent cycliza-
tion step.
With bispyrazole 10 in hand, attention turned toward the
construction of the required optically pure b-keto nitrile 9. At
the outset of this work, there was a concern about retaining the
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole
provided compound 13. Global deprotection in the presence of TFA
provided compound 10 in moderate yield. While this approach
could provide the required intermediate, we sought to develop a
more atom economical route to intermediate 10.

M. A. Labroli et al. / Tetrahedron Letters 57 (2016) 2601–2603
2603
Boc
N
N
Boc
N
Boc
N
Boc
N
Boc
N
N
N
N
a or b
(R)
O
N
c
OH
O
N
a
N
R
O
N
N
N
1
8
9
N
CN
Br
N
1
9:
N
NH2
8
NH2
O
N
2
1
2
0:
H
N
N
H
N
Boc
N
N
N
N
b
N
N
N
N
N
e
Br
N
d
N
NH
2
N
N
N
MK-8776
NH
2
NH
2
5
8
Scheme 6. Reagents and conditions: (a) NBS, CH
3 2 2
CN, 96%; (b) TFA, CH Cl , 90%.
Scheme 5. Reagents and conditions: (a) CDI, THF, 91%; (b) HN(OMe)MeꢀHCl, DIPEA,
2%; (c) LiHMDS, CH
CN, ꢁ78 °C, 63%; (d) compound 10, EtOH, 45 °C, 70%; (e) TFA,
CH Cl , 92%.
9
3
yielded compound 5 in 99% ee. With the results from entries c
and d from Table 1, attention then turned toward the final bromi-
nation and deprotection steps to yield MK-8776.
2
2
As mentioned above, bromination of compounds 5 and 6
Scheme 2) with NBS proved to be very inconsistent perhaps owing
stereochemical integrity during the preparation of this intermedi-
ate so a number of precursors were prepared to investigate this
potential issue. Furthermore, we felt it would be prudent to screen
various reaction conditions for the generation of 9 and analyze the
optical purity of the subsequent products. Starting with the com-
mercially available N-Boc-(R)-nipecotic acid 18, the intermediate
acyl imidazole intermediate 19 or Weinreb amide 20 could be pre-
pared under standard conditions as potential precursors to 9
shown in Scheme 5. Treatment of either 19 or 20 with the anion
of acetonitrile at low temperature afforded the requisite b-keto
nitrile 9 which could be isolated. Initial efforts to assay the optical
purity of 9 were not successful so the material was carried through
the cyclocondensation to afford 8 which could be converted to 5 by
treatment with TFA. As shown above in Scheme 2, compound 5
could be readily analyzed by chiral HPLC using a Chiralcel AD col-
umn to determine optical purity with the racemic material already
in hand.
Table 1 shows the results from a set of conditions used for gen-
eration of b-keto ester 9 which was then progressed through the
sequence shown in Scheme 5 to prepare compound 5. In the first
entry, treatment of 19 with the anion of acetonitrile at ꢁ78 °C fol-
lowed by warming to room temperature and subsequent quench-
ing led to 14% ee in compound 5. In light of this result, the
reaction was repeated (entry b) except keeping the reaction tem-
perature at ꢁ78 °C for 90 min to afford 5 in 84% ee. It was noted
that imidazole 19 was completely consumed by TLC after 30 min
at ꢁ78 °C so the low temperature reaction was repeated except
quenching at 30 min to afford 5 in 96% ee. Even in light of the very
good results for entry c (Table 1), we speculated that Weinreb
amide 20 may be less prone to racemization than acyl imidazole
(
to the basic nitrogen present in this material. Not only was the
bromination reaction not clean, removing all of the succinimide
by-product from the final compound proved to be somewhat chal-
lenging and labor intensive. However, treatment of 8 at 0 °C with a
solution of NBS in acetonitrile proved to be the most efficient way
to produce compound 21 in 96% yield shown in Scheme 6. The
reaction mixture was concentrated and the crude product redis-
3
solved in CHCl . The organic layer was washed with brine and
water to provide the title compound in >95% purity which can be
used directly in the final step. Treatment of Boc adduct 21 with
TFA then afforded the final compound, MK-8776, in excellent yield.
In summary, a highly convergent and efficient preparation of
the CHK1 inhibitor MK-8776 (SCH 900776) has been described.9
This route relies upon a highly efficient cyclocondensation reaction
of a optically pure b-keto nitrile with a substituted pyrazole to con-
struct the key pyrazolo[1,5-a]pyrimidine core in high enantiomeric
purity. The revised route to MK-8776 circumvents the need for a
late-stage chiral separation as well as the tedious protection/
deprotection chemistry found in the original medicinal chemistry
preparation. The key insights made into how to retain the chirality
of the b-keto nitrile fragment should allow the extension of this
chemistry toward the construction of other optically pure pyra-
zolo[1,5-a]pyrimidine compounds.
References and notes
1
2
3
.
.
.
(a) Sancar, A.; Lindsey-Boltz, L. A.; Unsal-Kacmaz, K.; Linn, S. Annu. Rev. Biochem.
2004, 73, 39; (b) Kastan, M. B.; Bartek, J. Nature 2004, 432, 316.
(a) Bucher, N.; Britten, C. D. Br. J. Cancer 2008, 98, 523; (b) Luo, Y.; Leverson, J. D.
Expert Rev. Anticancer Ther. 2005, 5, 333.
(a) Powell, S. N.; DeFrank, J. S.; Connell, P.; Eogan, M.; Preffer, F.; Dombkowski,
D.; Tang, W.; Friend, S. Cancer Res. 1995, 55, 1643; (b) Zhou, B.-B. S.; Elledge, S. J.
Nature 2000, 408, 433; (c) Li, Q.; Zhu, G.-D. Curr. Top. Med. Chem. 2002, 2, 939.
(a) Tao, Z.-F.; Lin, N.-H. Anti-Cancer Agents Med. Chem. 2006, 6, 377; (b)
Prudhomme, M. Recent Patents Anti-Cancer Drug Disc. 2006, 11, 55.
1
9 for this transformation. This hypothesis was based on the
assumption that the tetrahedral intermediate formed from the
addition of the anion of acetonitrile to Weinreb amide 20 would
prevent any racemization of the adjacent chiral center. Treatment
of 20 with the anion of acetonitrile at ꢁ78 °C for 30 min followed
by quenching and progression thru the sequence in Scheme 5
4
.
5. (a) Maugeri-Sacca, M.; Bartucci, M.; De Maria, R. Cancer Treat. Rev. 2013, 39, 525;
(b) Thompson, R.; Eastman, A. Br. J. Clin. Pharmacol. 2013, 76, 358; (c) Matthews,
T. P.; Jones, A. M.; Collins, I. Expert Opin. Drug Disc. 2013, 8, 621.
6.
Guzi, T. J.; Paruch, K.; Dwyer, M. P.; Labroli, M.; Shanahan, F.; Davis, N.; Taricani,
L.; Wiswell, D.; Seghezzi, W.; Penaflor, E.; Bhagwat, B.; Wang, W.; Gu, D.; Hsieh,
Y.; Lee, S.; Liu, M.; Parry, D. Mol. Cancer Ther. 2011, 10, 591.
Table 1
Acetonitrile anion addition conditions with optical purity of compound 5
7
.
(a) Dwyer, M. P.; Paruch, K.; Labroli, M.; Alvarez, C.; Keertikar, K.; Poker, C.;
Rossman, R.; Fischmann, T. O.; Duca, J. S.; Madison, V.; Parry, D.; Davis, N.;
Seghezzi, W.; Wiswell, D.; Guzi, T. J. Bioorg. Med. Chem. Lett. 2011, 21, 467; (b)
Labroli, M.; Paruch, K.; Dwyer, M. P.; Alvarez, C.; Keertikar, K.; Poker, C.;
Rossman, R.; Duca, J. S.; Fischmann, T. O.; Madison, V.; Parry, D.; Davis, N.;
Seghezzi, W.; Wiswell, D.; Guzi, T. J. Bioorg. Med. Chem. Lett. 2011, 21, 471.
Oldenziel, O. H.; Van Leusen, D.; Van Leusen, A. M. J. Org. Chem. 1977, 42, 3114.
Detailed procedures for the preparation of MK-8776 can be found in: Shumway,
S. D.; Toniatti, C.; Roberts, B. S.; Martin, M. M. WO 2013/039854 A1.
% ee of 5a
Entry
Substrate
Temp/time
a
b
c
19
19
19
20
ꢁ78 °C to rt
14
84
96
99
ꢁ78 °C/90 min
ꢁ78 °C/30 min
ꢁ78 °C/30 min
8.
.
d
9
a
Determined by Chiralcel AD column analysis.