An efficient synthesis of baricitinib

Article abstract of DOI:10.3184/174751916X14569294811333

A highly efficient method for the synthesis of baricitinib was developed. The starting material tert-butyl 3-oxoazetidine-1-carboxylate was converted to intermediate 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile via the Horner-Emmons reaction, deprotection of the N-Boc-group and a final sulfonamidation reaction. Then the nucleophilic addition reaction was carried out smoothly to afford the borate intermediate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene under reflux. Finally, the desired compound baricitinib was obtained by the Suzuki coupling reaction of 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine with the above borate intermediate. All compounds were characterised by IR, MS, ¹H NMR and ¹³C NMR. The overall yield in this synthetic route was as high as 49%. Moreover, this procedure is straightforward to carry out, has low cost and is suitable for industrial production.

Full text of DOI:10.3184/174751916X14569294811333

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JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 APRIL, 205–208
RESEARCH PAPER 205
An efficient synthesis of baricitinib
Jiaojiao Xub, Jin Caic, Junqing Chenc, Xi Zongc, Xuan Wuc, Min Jib* and Peng Wanga
aDepartment of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P.R. China
bSchool of Biological Sciences & Medical Engineering, Southeast University, Nanjing, 210096, P.R. China
cSchool of Chemistry & Chemical Engineering, Southeast University, Nanjing 210096, P.R. China
A highly efficient method for the synthesis of baricitinib was developed. The starting material tert-butyl 3-oxoazetidine-1-carboxylate
was converted to intermediate 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile via the Horner–Emmons reaction, deprotection of the
N-Boc-group and a final sulfonamidation reaction. Then the nucleophilic addition reaction was carried out smoothly to afford the borate
intermediate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene under reflux. Finally, the desired compound baricitinib was obtained
by the Suzuki coupling reaction of 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine with the above borate intermediate. All compounds were
characterised by IR, MS, 1H NMR and 13C NMR. The overall yield in this synthetic route was as high as 49%. Moreover, this procedure is
straightforward to carry out, has low cost and is suitable for industrial production.
Keywords: baricitinib, Janus kinase, synthesis, Suzuki cross-coupling
The Janus kinase (JAK) is a family of four tyrosine receptor
kinases that play a pivotal role in cytokine receptor signalling
pathways via their interaction with signal transducers and
activators of transcription proteins.1–6 The four JAK family
members are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2),
Janus kinase 3 (JAK3) and tyrosine kinase (TYK2), whose
lengths range from 120 to 140 kDa. It has been shown that JAK2
activation may be critical for tumour growth and progression,
indicating its selection as a therapeutic target. Moreover, since
JAK3 is required for immune cell development, targeting
JAK3 could be a useful strategy for generating a novel class
of immunosuppressant drugs. JAK1 and TYK2 have been
implicated in disease and immune suppression.
Over the past decade there have been extensive efforts to
identify and design novel small-molecule JAK inhibitors with
varied profiles of subtype selectivity to address unmet medical
needs (Fig. 1).7 Ruxolitinib is a Janus kinase inhibitor with
selectivity for subtypes JAK1 and JAK2. It was approved by
the U.S. Food and Drug Administration (FDA) for the treatment
of intermediate or high-risk myelofibrosis in November 2011.
Selective inhibitors of JAK are viewed as having considerable
potential as disease-modifying anti-inflammatory drugs for
the treatment of rheumatoid arthritis. Tofacitinib, which was
the first oral non-biological disease-modifying antirheumatic
drug, was approved for the management of rheumatoid arthritis
(RA) at the end of 2012.8 Baricitinib and filgotinib are being
evaluated in phase III and phase II clinical trials respectively for
the treatment of rheumatoid arthritis. Baricitinib (also known
as LY3009104 or INCB028050) is a novel and potent small
molecule inhibitor of the Janus kinase family of enzymes with
selectivity for JAK1 and JAK2. In in vitro studies baricitinib
inhibited JAK1 and JAK2 in the low nanomolar range, while
it demonstrated low inhibitory activity for JAK3 and moderate
activity for TYK2.9–13 The data from two phase III studies
showed that baricitinib can achieve impressive responses in RA
patients who have not responded well to established therapies.
Therefore, improvement in the preparation of baricitinib is of
practical significance.
Results and discussion
As shown in Scheme 1, Rodgers et al. have reported the first
synthetic route to baricitinib.14 tert-Butyl 3-oxoazetidine-
1-carboxylate (1) was employed as the starting material.
This was transformed to compound 2 by a Horner–Emmons
reaction, followed by deprotection of the N-Boc group in
acidic conditions. The intermediate 4 was obtained by the
sulfonamidation reaction of compound 3 with ethanesulfonyl
chloride. The other part of baricitinib was acquired by utilising
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5) as the starting
material. Compound 5 reacted with [2-(chloromethoxy)ethyl]
trimethylsilane (SEM-Cl) to afford the intermediate 6, which
was converted by reaction with 7 via the intermediate 8 to
4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-
pyrrolo[2,3-d]pyrimidine (9) via a Suzuki coupling reaction and
a hydrolysis reaction. After the nucleophilic addition reaction
and deprotection of the SEM group, baricitinib was obtained
O
S O
O
NC
N N
S
CN
N
N
O
N
N N
N
N
CN
O
N
O
N
N
N
N
N
N
H
HN
N
N
N
N
H
H
Tofacitinib
Ruxolitinib
Baricitinib
Filgotinib
Fig. 1 Structures of some selective inhibitors of JAK.
* Correspondent. E-mail: jimin@seu.edu.cn

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206 JOURNAL OF CHEMICAL RESEARCH 2016
O
O
P
O
O
O
O
CN
HCl
NH
N
N
O
NC
NC
tBuOK/THF
O
1
3
2
O
S
O S O
Cl
N
NC
O
DIPEA,
CH3CN
4
O
O
N
N
N N
O
B
Cl
Cl
O
Si
NaH/DMAC
7
O
Cl
N
N
N
K2CO3/Pd(PPh3)4
1-butanol/H2O
N
N
N
N
N
N
H
SEM
SEM
8
5
6
O
O
S
S
O
O
N
N
N NH
CN
CN
N N
N N
aq.HCl
1. LiBF
4/CH3CN
4
N
2. aq. NH4OH
DBU/CH3CN
N
N
N
N
SEM
N
H
N
SEM
N
N
9
Baricitinib
10
Scheme 1 The reported synthetic route to baricitinib.
Conclusion
through eight steps. This synthetic route had drawbacks of high
cost, low overall yield and the requirement of strict operating
conditions.
In summary, we have developed a straightforward and improved
approach for the synthesis of baricitinib. This novel synthetic
route employed tert-butyl 3-oxoazetidine-1-carboxylate (1)
and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5) as the starting
materials to afford baricitinib via the Horner–Emmons reaction,
deprotection of the N-Boc group, a sulfonamidation reaction,
a nucleophilic addition reaction and then a Suzuki coupling
reaction. The overall yield of this procedure was as high as 49%.
Moreover, this procedure has simple operating requirements
and low costs and is suitable for industrial production.
In order to improve the procedure, we designed a novel synthetic
route for the synthesis of baricitinib (Scheme 2). Similarly, we also
applied tert-butyl 3-oxoazetidine-1-carboxylate (1) as the starting
material. First, we optimised the preparation of compound 4.
In the Horner–Emmons reaction, NaH was used as the base
instead of t-BuOK, which led to a yield as high as 84%. Then
the deprotection of the N-Boc group was carried out smoothly
under trifluoroacetic acid (TFA) cleavage conditions to afford
compound 3, which was reacted with ethanesulfonyl chloride
without further purification. Next, the nucleophilic addition
reaction between compound 4 and 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-lH-pyrazole (11) proceeded successfully
in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
With the intermediate compound 12 in hand, we optimised the
conditions of the Suzuki coupling reaction with compound 5.
Several coupling systems were evaluated, such as Pd(PPh3)4–
K2CO3–t-butanol/H2O, Pd(PPh3)4–Na2CO3–t-butanol/H2O and
Pd(OAc)2–K2CO3–dioxane/H2O. The Pd(PPh3)4–CsF–t-butanol/
toluene/H2O system afforded the most satisfactory yield. Finally,
baricitinib was obtained efficiently and the overall yield was as
high as 49% based on tert-butyl 3-oxoazetidine-1-carboxylate
(1).
Experimental
All the reagents were obtained from commercial sources and used
without further purification. Melting points were determined on a RY-1
1
hot stage microscope and are uncorrected. H and 13C NMR spectra
were recorded on Bruker Avance DPX-300/500 MHz instrument in
DMSO-d6 or CDCl3. Chemical shifts (δ) are given in parts per million
(ppm) relative to TMS as an internal standard. Mass spectra (MS) were
obtained on an Agilent 1100 LC/MS spectrometer. IR spectra were
obtained on a PerkinElmer 1600 series FTIR spectrometer. Elemental
analyses were performed using an Arial Font Vario EL analyser. All
reactions were monitored by TLC on silica gel GF-254 glass plates.

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JOURNAL OF CHEMICAL RESEARCH 2016 207
O
O
P
O
O
O
O
CN
NH
TFA
N
N
O
NC
NC
rt
DCM,
rt
NaH/THF,
O
1
3
2
O
N
O
S
NH
N
N
B
O
N
O
S
O S O
Cl
DIPEA
O
O
11
N
B
CN
NC
O
O
DBU, IPA, reflux
/acetonitrile
12
4
Cl
N
O
S
O
N
N
N
CN
H
N N
5
Pd(PPh3)4,CsF, t-BuOH,
H2O,toluene, reflux
N
N
H
N
Baricitinib
Scheme 2 The novel synthetic route to baricitinib.
Synthesis of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2)
concentrated under reduced pressure. The concentrated residue was
then diluted with dichloromethane and was washed with aqueous
sodium chloride solution. The aqueous phase was back-extracted
with dichloromethane. The combined organic layers were dried over
Na2SO4 and the residue was purified using a silica gel column to afford
compound 4: Yield 192 mg (81%); off-white solid; m.p. 58–60 °C;
IR: 3294, 3066, 2978, 2222, 1702, 1321, 1142 cm–1. Anal. calcd for
C7H10N2O2S: C, 45.15; H, 5.41; N, 15.04; found: C, 45.32; H, 5.35; N,
15.21%. MS (m/z): 209 [M + Na]+; 1H NMR (300 MHz, CDCl3): δ 1.37
(m, J = 6.7 Hz, 3H), 3.04 (m, J = 7.4 Hz, 2H), 4.69 (t, J = 2.5 Hz, 2H),
4.77 (t, J = 2.8 Hz, 2H), 5.43 (t, J = 2.4 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6): δ 7.2, 42.6, 58.5, 58.9, 93.9, 114.9, 156.2, 168.6.
A suspension of NaH (260 mg, 11 mmol) in 25 mL of THF was
cooled in a 100 mL flask in an ice bath. A solution of diethyl
cyanomethylphosphonate (1.1 mL, 6.72 mmol, 1.15 equiv.) in THF
(20 mL) was added dropwise. The reaction was warmed to room
temperature for 1 h then cooled back to 0 °C for 1 h to give a milky
yellow solution. Then
a solution of tert-butyl 3-oxoazetidine-1-
carboxylate (1) (1.0 g, 5.84 mmol) in THF (10 mL) was added drop-wise
over 1 h. The resulting reaction mixture was stirred overnight, then
quenched with water and concentrated to remove THF. The resulting
aqueous solution was extracted with EtOAc. The combined organic
layers were washed with brine and dried with MgSO4. The filtrate
was concentrated down to a yellow oil which was purified by silica
chromatography using a gradient of 20–30% EtOAc/hexanes to afford
compound 2: Yield 939 mg (84%); m.p. 75–77 °C; IR (KBr): 2987, 2222,
1684, 1406, 1162 cm–1. Anal. calcd for C10H14N2O2: C, 61.84; H, 7.27; N,
14.42; found: C, 61.95; H, 7.46; N, 14.38%. MS (m/z): 217 [M + Na]+;
1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 4.62 (t, J = 1.9 Hz, 2H),
4.70 (t, J = 3.2 Hz, 2H), 5.38 (t, J = 2.3 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6): δ 27.9, 39.5, 79.4, 92.8, 115.2, 155.6, 158.4.
Synthesis of 2-{1-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (12)
A
mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-lH-
pyrazole (11) (156 mg, 0.80 mmol, 1.01 equiv.), compound 4 (149 mg,
0.80 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.061 mL,
0.408 mmol) in acetonitrile (20 mL) was heated at 60 °C for 4 h. After
cooling, the solvent was removed under reduced pressure. The residue
was purified by flash chromatography on a silica gel column eluting
with methanol in dichloromethane (0–60%) to afford the desired
compound 12: Yield 255 mg (84%); m.p. 120–122 °C; IR: 3280, 2978,
1639, 1554, 1369 cm–1. Anal. calcd for C16H25BN4O4S: C, 50.54; H,
6.63; N, 14.73; found: C, 50.67; H, 6.74; N, 14.62%. MS (m/z): 403 [M
+ Na]+; 1H NMR (300 MHz, DMSO-d6): δ 1.22 (t, J = 7.3 Hz, 3H), 1.27
(s, 12H), 3.19 (m, J = 7.3 Hz, 2H), 3.59 (s, 2H), 4.14 (d, J = 9.0 Hz, 2H),
4.44 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 8.35 (s, 1H); 13C NMR (75 MHz,
DMSO-d6): δ 4.6, 24.9, 39.5, 43.2, 55.5, 58.2, 83.2, 116.6, 135.8, 145.6.
Synthesis of 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile (4)
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl
3-(cyanomethylene)azetidine-1-carboxylate (2) (250 mg, 1.29
mmol) in dichloromethane (20 mL). The solution was stirred at room
temperature for 5 h. Then the reaction mixture was concentrated
under reduced pressure to dryness. The residue, which contains
the crude desired deprotection product 3, was then suspended in
acetonitrile (20 mL) and cooled to 0 °C. N,N-Diisopropylethylamine
(DIPEA) (1.12 mL, 6.44 mmol, 5 equiv.) was then slowly added while
keeping the internal temperature below 5 °C. Then ethanesulfonyl
chloride (EtSO2Cl) (0.184 mL, 1.94 mmol, 1.5 equiv.) was added over
1 h while keeping the internal temperature below 5 °C. The resulting
reaction mixture was stirred overnight at room temperature and then
Synthesis of 2-[3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-
1-yl)-1-(ethylsulfonyl)azetidin-3-yl]acetonitrile (baricitinib)
To a flask were added 2-{1-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

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208 JOURNAL OF CHEMICAL RESEARCH 2016
2
J.J. Kulagowski, W. Blair, R.J. Bull, C. Chang, G. Deshmukh, H.J. Dyke,
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L.J. Farmer, M.W. Ledeboer, T. Hoock, M.J. Arnost, R.S. Bethiel, Y.L.
Bennani, J.J. Black, C.L. Brummel, A. Chakilam, W.A. Dorsch, B. Fan,
J.E. Cochran, S. Halas, E.M. Harrington, J.K. Hogan, D. Howe, H. Huang,
D.H. Jacobs, L.M. Laitinen, S. Liao, S. Mahajan, V. Marone, G. Martinez-
Botella, P. McCarthy, D. Messersmith, M. Namchuk, L. Oh, M.S. Penney,
A.C. Pierce, S.A. Raybuck, A. Rugg, F.G. Salituro, K. Saxena, D. Shannon,
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(12) (870 mg, 2.3 mmol, 1.1 equiv.), 4-chloro-7-H-pyrrolo[2,3-d]
pyrimidine (5) (290 mg, 0.19 mmol), caesium fluoride (1120 mg),
tetrakis(triphenylphosphine)palladium (240 mg, 0.1 equiv.), tert-
butanol (10 mL), water (10 mL) and toluene (10 mL) at ambient
temperature. The resulting reaction mixture was heated to reflux
under nitrogen for 48 h. Then the reaction mixture was cooled to
room temperature and filtered through a Celite bed. The Celite bed
was washed with ethyl acetate and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were concentrated
under reduced pressure to remove solvents and the crude product was
purified by flash chromatography on a silica gel column eluting with
methanol in dichloromethane (0–60%) to afford baricitinib: Yield 560
mg (84%); m.p. 193–195 °C; IR: 3203, 3113, 2998, 2847, 2363, 1584,
1328, 1137 cm–1. Anal. calcd for C16H17N7O2S: C, 51.74; H, 4.61; N,
26.40; found: C, 51.91; H, 4.49; N, 26.57%. MS (m/z): 372 [M + H]+;
1H NMR (300 MHz, DMSO-d6): δ 1.25 (t, J = 7.3 Hz, 3H), 3.23 (m, J
= 7.3 Hz, 2H), 3.69 (s, 2H), 4.24 (d, J = 9.0 Hz, 2H), 4.61 (d, J = 9.0 Hz,
2H), 7.08 (s, 1H), 7.62 (s, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.92 (s, 1H),
12.12 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 7.4, 24.9, 39.3, 43.4,
58.5, 99.9, 113.0, 116.6, 126.9, 129.5, 139.9, 149.3, 150.9, 152.2.
3
4
5
6
7
The authors thank the NSFC (No. 81501529), the Fundamental
Research Funds for the Central Universities (2015PY001), the
National High-Tech Research and Development Project (863
Project, 2013AA032205), Industry Project of Jiangsu Science-
technology Support Plan (BE2013840), and the Science and
Technology Development Programme of Suzhou (ZXY201412)
for financial support.
8
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Received 16 January 2016; accepted 4 February 2016
Paper 1603848 doi: 10.3184/174751916X14569294811333
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