Synthesis and Characterization of Compounds Potentially Related to the Janus Kinase Inhibitor Baricitinib

Article abstract of DOI:10.1134/S1070428019100166

Nine compounds potentially related to the Janus kinase inhibitor Baricitinib have been identified, synthesized by conventional methods, and characterized by IR, ¹H and ¹³C NMR, and mass spectral data.

Full text of DOI:10.1134/S1070428019100166

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 10, pp. 1569–1574. © Pleiades Publishing, Ltd., 2019.
Synthesis and Characterization of Compounds Potentially
Related to the Janus Kinase Inhibitor Baricitinib
a, b
a
b
b
b
S. R. Dasari , N. Seelam ,* S. Jayachandra , L. R. Vadali , E. R. Yerva ,
c
b
S. Tondepu , and M. K. Gadakar
a
Department of Chemistry, Koneru Lakshmaiah Education Foundation,
Vaddeswaram, Guntur, Andhra Pradesh, India
*
e-mail: nareshvarma.klu@gmail.com
b
Mylan Laboratories Ltd., Hyderabad, Telangana, India
c
Department of Chemical Engineering, Vignan’s Foundation for Science, Technology, and Research,
Vadlamudi, Guntur, Andhra Pradesh, India
Received April 3, 2019; revised August 15, 2019; accepted August 17, 2019
Abstract—Nine compounds potentially related to the Janus kinase inhibitor Baricitinib have been identified,
1
13
synthesized by conventional methods, and characterized by IR, H and C NMR, and mass spectral data.
Keywords: Baricitinib, rheumatoid arthritis, synthesis, characterization, Baricitinib-related substances.
DOI: 10.1134/S1070428019100166
Baricitinib is a very recently proposed active
pharma ingredient used for the treatment of all levels
of rheumatoid arthritis [1]. It has been invented and is
under marketing by Incyte Corporation and Eli Lilly
0.15% of any of its related substances [7] (the impurity
levels may vary depending on the maximum daily
dosage). To attain the required purity level of
Baricitinib, an efficient purification procedure should
be developed. To achieve this goal, prior knowledge of
the structure and physical and chemical properties of
the related substances plays a vital role. Therefore,
possible Baricitinib related substances should be iden-
tified by conventional methods, isolated by various
isolation techniques, characterized by different ana-
lytical methods, and synthesized easily by traditional
schemes. Once the standard samples of all possible
related substances have been prepared and character-
ized, we should make sure that the quantitative levels
of each of those known related substances is below
&
Co. under the trade name Olumiant. The drug has
been approved first in Europe [2] and then in the
United States of America [3] with a maximum daily
dosage of 2 mg. Various methods for the synthesis of
Baricitinib have been reported [4–6]. Scheme 1 out-
lines one of the described synthetic approaches
adopted as an efficient and commercially viable
method for the preparation of Baricitinib.
During the synthesis of Baricitinib according to
Scheme 1, many other compounds eluting very closely
to Baricitinib were detected by thin-layer chromatog-
raphy. All these compounds (1–9) were isolated by
column chromatography, characterized by mass, IR,
0
.15% in a given sample of Baricitinib. In view of the
above stated, the present work was aimed as synthe-
sizing Baricitinib related substances 1–9 and charac-
terizing them by various spectral methods like IR spec-
1
13
and H and C NMR spectra, and shown to be
structurally related to Baricitinib; they were called
1
13
troscopy, H and C NMR, and mass spectrometry.
“
Baricitinib related substances.” It is now evident that
the process of preparation of Baricitinib could be
accompanied by generation of its related substances
which could be mixed up with the required actual
active pharma ingredient. In keeping with the latest
ICH (International Conference on Harmonization)
guidelines, any drug proposed for use in human
medication should normally contain no more than
Compounds 1–9 were synthesized on a multigram
scale employing traditional synthetic methodologies
and were characterized by various analytical tech-
niques (Schemes 2–4). Alcohol 1 was identified in the
reaction 14 → 15 (Scheme 1) and was prepared on
a 10-g scale as per Scheme 2 [8]. Imidic ester 2, ester
3, acid 4, and amide 5 were also identified in the
1
569

1
570
DASARI et al.
Scheme 1.
Me
N
OEt
Me
Me
N
EtO
O
B
Me
Me
Cl
N
Cl
N
N
Me
O
ClCH OC(O)Bu-t
N
2
N
i
N
ii
N
O
O
N
N
N
N
H
Bu-t
Bu-t
O
O
1
0
11
12
NC
NC
N
SO Et
N
SO Et
2
2
N
NH
N
N
N
N
N
SO Et
2
NC
iii
iv
v
N
N
N
O
O
N
N
N
N
N
N
H
Bu-t
Bu-t
O
O
1
3
14
15, Baricitinib
Reaction conditions: i: NaOH, DMF; ii: Pd(PPh
3
)
4
, K
2
3
CO ; iii: aq. HCl, THF, aq. NaOH; iv: DBU, DMF, MeCN;
v: LiOH, H
2
O, MeCN.
transformation of 14 to 15 and were prepared in
multigram quantities as shown in Scheme 3 [9–11].
Compounds 6–9 were identified in the subsequent
conversions of 10–14 and were prepared according to
Scheme 4.
Prior awareness of highly abundant related sub-
stances and their possible formation pathways will be
helpful to prepare Baricitinib with highest yield and
purity. These will in turn impart robustness to the syn-
thetic process of Baricitinib preparation on the com-
mercial scale. Also, identification, synthesis, and char-
acterization of Baricitinib related substances make its
regulatory aspects easier to handle. So, our attempt to
prepare and characterize the Baricitinib related sub-
stances may add useful knowledge for researchers.
EXPERIMENTAL
All chemicals were purchased from commercial
suppliers and were used without further purification.
All reactions were performed under inert nitrogen
atmosphere employing dry solvents. Precoated TLC
silica gel plates (Kieselgel 60 F , Merck) were used
2
54
for monitoring reactions, and spots were visualized
under UV lamp (λ 254 nm). Purification was per-
formed by column chromatography using silica gel
(
particle size 60–120 mesh, Merck). The IR spectra
were recorded in KBr on a Perkin–Elmer 400 FTIR
1
13
spectrometer. The H NMR and C NMR spectra were
recorded in CDCl or DMSO-d on a Bruker Avance
3
6
1
spectrometer at 300 or 500 MHz for H with reference
to TMS. The mass spectra were recorded using Waters
Xevo TQS LC/MS/MS system. Elemental analysis was
performed with a Thermo Finnigan Flash EA1112
elemental analyzer.
Scheme 2.
NC
N
SO Et
2
N
N
[
1-(Ethanesulfonyl)-3-{4-[7-(hydroxymethyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}-
azetidin-3-yl]acetonitrile (1). A mixture of Baricitinib
(
CH O) , Et N
2 n 3
MeCN, reflux
1
5
8
0%
(
15) (10.0 g, 0.027 mol), paraformaldehyde (16.2 g,
N
0
.54 mol of CH O), triethylamine (54.6 g, 0.54 mol),
2
N
N
and acetonitrile (100 mL) was heated to 80°C and
stirred at that temperature for ~24 h. When the reaction
was complete (TLC), excess paraformaldehyde was
OH
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

SYNTHESIS AND CHARACTERIZATION OF COMPOUNDS POTENTIALLY RELATED
1571
Scheme 3.
HN
O
MeO
MeO
N
SO Et
H
2
SO
4
N
SO Et
2
2
NaOH, MeOH
MeOH–H
65°C, 2 h
O–MeCN
2
N
N
N N
room temp., 30 h
1
4
2
0–25%
N
N
N
N
N
N
H
H
2
3
O
HO
N
SO Et
2
(
1) NaOH, H O–THF, room temp., 24 h
2
N N
(
2) concd. aq. HCl
N
N
H
N
4
O
H N
2
N
SO Et
2
N
N
Aq. NH , EtOH, 60°C, 24 h
3
N
N
H
N
5
Scheme 4.
Me
N
OEt
N
Me
Me
EtO
O
Cl
N SO Et
N
N
B
Me
Me
2
Me
O
NC
N
N
i
ii
1
0
N
N
N
N
N
N
NC
SO
Et
2
NC
SO Et
2
6
7
NC
N
SO Et
2
N
NH
N N
N SO Et
2
NC
iii
N
i
N
N
N
N
N
N
N
SO
NC
SO
Et
2
NC
Et
2
8
9
Reaction conditions: i: (DBU), MeCN, 0°C; ii: Pd(PPh
3 4 2 3 2
) , K CO , H O, 1,4-dioxane, 80°C;
iii: 2N aq. HCl, THF, room temp., NaOH.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

1
572
DASARI et al.
filtered off, the filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel
column chromatography using ethyl acetate–hexane
acetic acid (4). A mixture of 3 (10.0 g, 0.025 mol) and
sodium hydroxide (3.0 g, 0.075 mol) in 10% aqueous
tetrahydrofuran (100 mL) was stirred for ~6 hours at
room temperature (TLC). The solvent was evaporated,
the residue was dissolved in 50 mL of water, the solu-
tion was acidified to pH 3–4 with concentrated aque-
ous HCl, and the mixture was stirred for ~2 h at room
temperature. The solid product was isolated by filtra-
(
1:1) as eluent. Yield 5.0 g (46%), white solid. IR
–
1
spectrum, ν, cm : 3142, 2251, 1729, 1589, 1574,
1
1
153, 1141. H NMR spectrum (300 MHz, DMSO-d ),
6
δ, ppm: 1.25 t (3H, J = 7.4 Hz), 3.24 q (2H, J =
.5 Hz), 3.72 s (2H), 4.24 d (2H, J = 9.0 Hz), 4.61 d
2H, J = 9.0 Hz), 5.63 d (2H, J = 7.2 Hz), 6.67 t (OH,
J = 7.4 Hz), 7.16 d (1H, J = 3.9 Hz), 7.74 d (1H, J =
7
(
1
tion and dried. Yield 8.0 g (83%). H NMR spectrum
(500 MHz, DMSO-d ), δ, ppm: 1.24 t (3H, J = 7.0 Hz),
6
3
.9 Hz), 8.51 s (1H), 8.78 s (1H), 8.96 s (1H).
3.14 s (2H), 3.21 q (2H, J = 7.5 Hz), 4.30 d (1H, J =
9.0 Hz), 4.35 d (1H, J = 9.0), 4.52 d (2H, J = 9.0 Hz),
7.02 d.d (1H, J = 3.5, 1.7 Hz), 7.55 d.d (1H, J = 3.5,
2.6 Hz), 8.41 s (1H), 8.68 s (1H), 8.76 s (1H),
1
3
C NMR spectrum (300 MHz, DMSO-d ), δ , ppm:
6
C
1
1
5
51.00, 150.75, 149.68, 139.97, 129.75, 129.54,
21.96, 116.68, 113.51, 100.13, 66.43, 59.77, 58.54,
6.10, 43.30, 26.84, 7.44. Mass spectrum: m/z 402.05
1
3
12.13 br.s (1H). C NMR spectrum (500 MHz,
+
[M + H] . Found, %: C 51.25; H 5.10; N 24.12; S 7.85.
CDCl ), δ , ppm: 175.4, 153.27, 150.0, 149.7, 140.3,
3
C
C H N O S. Calculated, %: C 50.86; H 4.77;
129.90, 128.23, 114.75, 112.62, 99.99, 59.63, 56.74,
1
7
19
7
3
N 24.42; S 7.99.
43.57, 26.94, 7.45. Mass spectrum: m/z 391.20
+
[M + H] . Found, %: C 49.60; H 4.97; N 21.26; S 8.67.
Methyl 2-{1-(ethanesulfonyl)-3-[4-(7H-pyrrolo-
C H N O S. Calculated, %: C 49.22; H 4.65;
[
2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-
16 18
6
4
N 21.53; S 8.21.
3
-yl}acetimidate (2). A suspension of 14 (25.0 g,
0
.051 mol) and sodium hydroxide (0.2 g, 0.005 mol) in
2-{1-(Ethanesulfonyl)-3-[4-(7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}-
acetamide (5). A suspension of 3 (10.0 g, 0.025 mol)
in 20% aqueous ammonia (100 mL) was heated to
60°C and stirred for ~2 h at that temperature (TLC).
The mixture was cooled to room temperature and
stirred for 2 h more, and the solid product was filtered
methanol (125 mL) was stirred at room temperature for
30 h (TLC). The crude product was isolated by
~
filtration. In contained 20–25% of 2 (according to the
LC/MS data) which was isolated by preparative HPLC.
Mass spectrum: m/z 404.14 [M + H] .
+
Methyl 2-{1-(ethanesulfonyl)-3-[4-(7H-pyrrolo-
1
off. Yield 8.0 g (80%). H NMR spectrum (500 MHz,
[
2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-
-yl}acetate (3). A suspension of 2 (25.0 g, 0.062 mol)
in a mixture of methanol with water and acetonitrile
8:8:2, 250 mL) containing a catalytic amount of sul-
DMSO-d ), δ, ppm: 1.24 t (3H, J = 7.0 Hz), 3.16 s
3
6
(
4
(
(
2H) 3.22 q (2H, J = 7.0 Hz), 4.38 d (2H, J = 9.0 Hz),
.50 d (2H, J = 9.0 Hz), 7.0 s (1H), 7.29 s (NH), 7.55 s
1H), 7.84 s (NH), 8.63 s (1H), 8.86 m (1H), 8.98 s
(
furic acid was stirred at 65°C for ~2 h (TLC). The
mixture was cooled to room temperature and stirred for
2
precipitate was filtered off and dried at 45–50°C for
5
3
1
3
1H). C NMR spectrum (500 MHz, CDCl ), δ , ppm:
3 C
1
1
2
4
70.4, 152.27, 151.0, 149.4, 140.02, 129.67, 126.97,
16.75, 113.16, 99.99, 58.63, 56.14, 43.47,
h more complete precipitation of the product. The
+
–
1
6.94, 7.48. Mass spectrum, m/z: 390.20 [M + H] ,
h. Yield 25.0 g (100%). IR spectrum, ν, cm : 3198,
+
1
12.2 [M + Na] .
119, 2998, 1738, 1584. H NMR spectrum (300MHz,
DMSO-d ), δ, ppm: 1.25 t (3H, J = 7.4 Hz), 3.25 q
2-[3-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-
-yl)-1-(ethanesulfonyl)azetidin-3-yl]acetonitrile (6).
6
(
2H, J = 7.5 Hz), 3.54 s (3H), 3.46 s (2H), 4.31 d (2H,
J = 9.0 Hz), 4.54 d (2H, J = 9.0 Hz), 7.06 d.d (1H, J =
.5, 1.7 Hz), 7.61 d.d (1H, J = 3.5, 2.6 Hz), 8.40 s
1H), 8.70 s (1H), 8.83 s (1H), 12.13 br.s (1H, NH).
7
A suspension of 10 (10.0 g, 0.065 mol) and
-[1-(ethanesulfonyl)azetidin-3-ylidene]acetonitrile
12.12 g, 0.065 mol) in acetonitrile (50 mL) was
cooled to 0°C, 1,8-diazabicyclo[5.4.0]undec-7-ene
DBU, 0.50 g, 0.00325 mol) was added, and the
mixture was stirred for ~3 h (TLC). Diisopropyl ether
50 mL) was added, and the solid product was filtered
3
2
(
(
1
3
C NMR spectrum (300 MHz, DMSO-d ), δ , ppm:
6
C
1
1
69.52, 152.16, 150.91, 149.61, 139.42, 129.39, 126.82,
(
12.95, 99.94, 59.51, 56.83, 51.65, 42.95, 41.06, 7.43.
+
Mass spectrum: m/z 405.04 [M + H] . Found, %:
(
C 51.37; H 5.32; N 20.52; S 7.80. C H N O S. Cal-
1
7
20
6
4
off, washed with diisopropyl ether (50 mL), and dried.
1
culated, %: C 50.48; H 4.98; N 20.78; S 7.93.
-{1-(Ethanesulfonyl)-3-[4-(7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}-
Yield 18.0 g (81%), pale yellow solid. H NMR spec-
2
trum (500 MHz, CDCl ), δ, ppm: 1.41 t (3H, J =
3
7.0 Hz), 3.09 q (2H, J = 7.5 Hz), 3.42 s (2H), 4.30 d.d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

SYNTHESIS AND CHARACTERIZATION OF COMPOUNDS POTENTIALLY RELATED
1573
(
2H, J = 1.0, 8.0 Hz), 4.68 d (2H, J = 9.5 Hz), 6.74 d
1H, J = 4.0 Hz), 7.27 d (1H, J = 2.5 Hz), 8.61 s (1H).
perature for ~1 h, and the solid precipitate was filtered
1
(
off and dried. Yield 8.0 g (100%). H NMR spectrum
(500 MHz, DMSO-d ), δ, ppm: 1.24 t (3H, J = 7.5 Hz),
1
3
C NMR spectrum (500 MHz, CDCl ), δ , ppm:
6
3
C
1
5
3
52.72, 150.70, 149.90, 125.93, 117.99, 115.17, 100.91,
3.22 q (2H, J = 7.5 Hz), 3.62 s (2H), 4.32 d (2H, J =
9.0 Hz), 4.67 d (2H, J = 9.0 Hz), 7.20 d (1H, J =
4.0 Hz), 7.83 d (1H, J = 4.0 Hz), 8.37 s (1H), 8.71 s
8.36, 52.38, 46.47, 27.20, 7.62. Mass spectrum, m/z:
+
+
40.1 [M + H] , 362.1 [M + Na] .
1
3
(
1H), 8.73 s (1H), 13.5 s (1H, NH). C NMR spectrum
2
-({3-[4-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl]-7H-
(
500 MHz, DMSO-d ), δ , ppm: 151.58, 151.05,
6
C
pyrrolo[2,3-d]pyrimidin-7-yl}azetidin-3-yl)aceto-
nitrile (7). Potassium carbonate (16.1 g, 0.116 mol)
and water (30 mL) were added at room temperature to
a suspension of 6 (10.0 g, 0.029 mol) and 1-(1-ethoxy-
ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1
1
50.35, 138.92, 129.79, 127.12, 119.89, 116.80, 113.75,
00.85, 58.71, 58.44, 52.28, 43.32, 26.93, 7.46. Mass
+
spectrum: m/z 372.2 [M + H] .
2-[3-(4-{1-[(3-(Cyanomethyl)-1-(ethanesulfonyl)-
azetidin-3-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]-
pyrimidin-7-yl)-1-(ethanesulfonyl)azetidin-3-yl]-
acetonitrile (9). 1,8-Diazabicyclo[5.4.0]undec-7ene
1
H-pyrazole (7.42 g, 0.029 mol) in 1,4-dioxane
(
100 mL). The two-phase mixture was degassed with
nitrogen for ~30 min, and tetrakis(triphenylphos-
phine)palladium(0) (0.60 g, 0.52 mmol) was added.
The mixture was heated to 80°C and stirred at that
temperature for 10–12 h (TLC). The mixture was then
cooled to room temperature and filtered, the aqueous
layer was separated from the filtrate, and the organic
layer was mixed with ethyl acetate (100 mL), washed
with water (2×100 ml), and concentrated under
reduced pressure. The oily residue was treated with
diisopropyl ether (100 mL), the mixture was stirred for
(
DBU, 0.01 g, 0.68 mmol) was added with stirring at
0
2
–5°C to a suspension of 8 (10.0 g, 0.027 mol) and
-[1-(ethanesulfonyl)azetidin-3-ylidene]acetonitrile
(
5.01 g, 0.027 mol) in acetonitrile (80 mL). The mix-
ture was stirred for ~3 h (TLC) and diluted with diiso-
propyl ether (100 mL), the precipitate was filtered off
and taken in additional diisopropyl ether (50 mL), the
mixture was stirred, and the precipitate was filtered off
1
and dried. Yield 12.0 g (80%), white solid. H NMR
spectrum (300 MHz, DMSO-d ), δ, ppm: 1.21–1.29 m
2
h at room temperature, and the precipitate was
6
(
4
(
8
6H), 3.18–3.28 m (4H), 3.62 s (2H), 3.70 s (2H),
.28 d (4H, J = 9.0 Hz), 4.65 d (4H, J = 9.0 Hz), 7.29 d
1H, J = 3.6 Hz), 7.91 d (1H, J = 3.6 Hz), 8.52 s (1H),
filtered off, washed with (i-Pr) O (20 mL), and dried.
Yield 10.0 g (77%), yellow solid. H NMR spectrum
2
1
(
500 MHz, CDCl ), δ, ppm: 1.20 t (3H, J = 4.5 Hz),
3
1
3
.78 s (1H), 8.99 s (1H). C NMR spectrum
1
.42 t (3H, J = 7.5 Hz), 1.76 d (3H, J = 6.0 Hz), 3.08 q
(
300 MHz, DMSO-d ), δ , ppm: 150.98, 150.47,
6 C
(
2H, J = 7.5 Hz), 3.46 s (2H), 3.42–3.44 m (1H), 3.52–
1
1
2
50.41, 140.06, 130.01, 127.56, 121.64, 116.67, 116.63,
13.96, 100.84, 56.16, 52.32, 43.35, 43.31, 26.91,
6.86, 7.43. Mass spectrum: m/z 558.09 [M + H] .
3
9
3
.55 m (1H), 4.31 d (2H, J = 10.0 Hz), 4.72 d (2H, J =
.0 Hz), 5.61 q (1H, J = 6.0 Hz), 6.86 d (1H, J =
.5 Hz), 7.25 d (1H, J = 4.0 Hz), 8.25 s (1H), 8.40 s
+
13
(
1H), 8.76 s (1H). C NMR spectrum (500 MHz,
ACKNOWLEDGMENTS
CDCl ), δ , ppm: 151.87, 151.54, 150.53, 138.74,
3
C
1
6
27.08, 124.87, 121.75, 115.45, 114.49, 101.36, 87.97,
The authors thank their research supervisors for
4.33, 58.60, 52.20, 46.59, 27.16, 22.1, 14.72, 7.73.
providing the required facilities. We also thank Department
of Chemistry, Koneru Lakshmaiah Education Foundation,
and Mylan Laboratories Ltd. for their help in performing
this study.
+
Mass spectrum: m/z 420.136 [M + H] .
2
-{1-(Ethanesulfonyl)-3-[4-(1H-pyrazol-4-yl)-
7
H-pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-3-yl}
acetonitrile (8). Compound 7 (10.0 g, 0.023 mol) was
dissolved in tetrahydrofuran (60 mL), 2 N aqueous
hydrochloric acid (30 mL) was added at room tempera-
ture, and the mixture was stirred for ~24 h (TLC).
Tetrahydrofuran was distilled off, the aqueous residue
was adjusted to pH 10–12 by adding 30% aqueous
sodium hydroxide at a temperature not exceeding
CONFLICT OF INTERESTS
The authors declare the absence of conflict of interests.
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2
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filtered off. The wet cake was taken in diisopropyl
ether (100 mL), the mixture was stirred at room tem-
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