Short enantioselective total synthesis of (+)-tofacitinib

Article abstract of DOI:10.1016/j.tetlet.2021.152838

An enantioselective total synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor has been achieved from the readily available 4-piperidone. Proline catalysed hydroxylation is the key step for the synthesis of enantiopure 1-benzyl-4-methylpiperidin-3-ol.

Full text of DOI:10.1016/j.tetlet.2021.152838

Tetrahedron Letters 67 (2021) 152838
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Short enantioselective total synthesis of (+)-tofacitinib
Kishor D. Mane a,b, Rohit B. Kamble a,b, Gurunath Suryavanshi a,b,
⇑
a
Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India
Academy of Scientific and Innovative Research, Ghaziabad 201 002, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective total synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific
inhibitor has been achieved from the readily available 4-piperidone. Proline catalysed hydroxylation is
the key step for the synthesis of enantiopure 1-benzyl-4-methylpiperidin-3-ol.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 24 November 2020
Revised 6 January 2021
Accepted 8 January 2021
Available online 1 February 2021
Keywords:
L
-Proline
Piperidone
Aminohydroxylation
Hydrogenation
Introduction
substituted piperidines and amino deazapurine core as shown in
Fig. 1. Also, it shows promising clinical activities against autoim-
Substituted piperidines are the most accessible structural
motifs found among the biologically active N-heterocycles which
occurred naturally as well as synthetically [1]. It has become the
most reputed and impressive core structure as it is present in 72
small drug molecules having piperidine as active site [2]. Due to
the impact of piperidines in pharmaceutical industry it has
attracted the attention of chemists towards its synthesis [3]. The
Janus protein tyrosine kinase also known as jakinibs, are a type
of medication that act for inhibiting the movement of one or more
of the Janus kinase family of enzymes (JAK1, JAK2 and JAK3)
thereby interrupting with the JAK-STAT signalling pathway [4].
Hence it has become an important task to develop JAK inhibitors
which will prevent such uncontrolled inflammation [5].
In recent studies, 3, 4-disubstituted piperidines has shown a
promising candidate as JAK inhibitors [6a]. Whereas in 2012, tofac-
itinib (1) became the first JAK inhibitor drug approved by the Food
and Drug Administration (FDA) for the treatment of rheumatoid
arthritis, also in 2017 it was further approved for the treatment
of active rheumatoid arthritis (RA) [6b], psoriatic arthritis [6c],
and ulcerative colitis [6d].
mune related diseases such as psoriasis, inflammatory bowel dis-
ease and Crohn’s disease [8].
Due to the increasing importance of tofacitinib in medicinal and
pharmaceutical fields, several synthetic approaches have been well
reported in the literature [9a]. Among the reported methods,
asymmetric synthesis of tofacitinib is rarely explored [9b-d].
In 2013, Maricán et al. reported the preparation of key synthetic
intermediate tert-butyl-(3S,4R)-3-hydroxy-4-methyl piperidine-1-
carboxylate from (S)-5-hydroxypiperidin-2-one in 6 steps [10].
Preliminary the key steps of this route are selenoxide elimination,
Grignard methyl cuprate addition, with an overall yield of 18%.
Initially, Ripin and co-workers from Pfizer has developed a syn-
thetic route for the preparation of key intermediate 2 from 4-pico-
line, followed by late stage resolution to achieve the enantiomeric
purity [11a]. In 2017, Uang et al. accomplished the formal asym-
metric synthesis of tofacitinib via a stereoselective Michael addi-
tion of the corresponding enolate of chiral 1,3-dioxolanone to
methyl crotonate. The enantioselectivity was introduced by using
chiral auxiliary i.e. homochiral 1,3-dioxolanon synthesized from
derivative of camphor sulfonic acid and glycolic acid [9d].
For the synthesis of enantiopure piperidine moiety above
method requires late stage resolution techniques which results in
the loss of yield. Furthermore, use of chiral auxiliary and harsh
reaction conditions make the above approaches impractical.
Hence, to overcome this limitation, we have developed an enan-
tioselective synthesis of key intermediate 2a with 18% overall yield
and high enantiopurity of the 2a was achieved by hydrolytic
It is a promising immunosuppressant, developed by Pfizer and
approved for treatment during the organ transplant rejection [7].
Tofacitinib (CP-690,550) (1) with two chiral centers having the
⇑
Corresponding author at: Chemical Engineering & Process Development Divi-
sion, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra
4
11008, India.
E-mail address: gm.suryavanshi@ncl.res.in (G. Suryavanshi).
https://doi.org/10.1016/j.tetlet.2021.152838
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

K.D. Mane, R.B. Kamble and G. Suryavanshi
Tetrahedron Letters 67 (2021) 152838
ric
a-aminoxylation reaction using
L-proline as organocatalyst and
nitrosobenzene as aminoxylating source in DMF under N
sphere for 62 hrs, followed by one carbon Wittig reaction using
methyl triphenylphosphonium iodide (CH PPh I) and t-BuOK as
2
atmo-
3
3
base in THF for 12 hrs which gives intermediate 7 as shown in
Scheme 3.
After consumption of starting material, the OAN bond cleavage
of intermediate 7 was achieved in situ by addition of CuSO
4
ꢀ5H
2
O
in the reaction mixture and kept for another 12 h to give the cor-
responding chiral allylic alcohol 4 in 47% yield over three steps
with 97% ee [14].
Fig. 1. Structure of Tofacitinib and Key Intermediate.
Furthermore, the formed allylic alcohol 4 was subjected for
diastereoselective hydrogenation reaction using 1 atm pressure
of hydrogen and 10% Pd on carbon to form the compound 2a in
Scheme 1. Various Routes for synthesis of intermediate 2 from pyridines.
kinetic resolution starting from crotyl alcohol as shown in
Scheme 1 [12b].
The presence of enantiopure piperidine moiety as a core struc-
ture in tofacitinib and our continuous efforts towards the synthesis
of these moieties [12], we have outlined a retro synthetic approach
for the tofacitinib (1). As shown in Scheme 2, the synthesis of tofac-
itinib (1) could be accomplished from stereoselective inversion of
Scheme 3. Synthesis of Enantiopure Hydroxypiperidine via Proline Catalysed
aminoxylation; Reaction Conditions: (a) BnBr, K CO , H O:CHCl (1:1), 12 h, rt 87%;
(b) (i) -proline, PhNO, DMF, 0 °C, 62 h; (ii) CH PPh I, t-BuOK, LiCl (1.1 eq.), THF,
0 °C; (c) CuSO ꢀ5H O (30 mol %), MeOH, 25 °C, 12 h; (d) 10% Pd/C, H (1 atm),
AcOEt, 5 h, rt, 93%.
a-
1
-benzyl-4-methylpiperidin-3-yl
methanesulfonate
2b
via
2
3
2
3
nucleophilic substitution reaction with N-methyl dezapurine
amine 3. Further, the key intermediate 2a can be synthesized from
the N-protected piperidone 5 by using proline catalysed one pot
L
3
3
5
4
2
2
a-aminoxylation and Wittig reaction, followed by reduction of
allylic alcohol 4.
Our approach towards the synthesis of key intermediate 2a
commences from N-benzyl protection of 4-piperidone 6 under
basic condition using K CO , BnBr in H O and chloroform, gives
2 3 2
N-benzyl protected 4-piperidone 5 in 87% yield [13]. The com-
pound 5 was then subjected for direct proline-catalyzed asymmet-
Scheme 4. Synthesis of (+)-Tofacitinib: (a) MsCl, TEA, DCM, 0 °C, 1 h, 97%; (b) 3,
CO , DMF, 60 °C, 12 h, 81%; (c) 20 wt% Pd(OH) , H (1 atm), TFA, MeOH, 45 °C 12 h
then, ClCOCH CN, DCM, TEA, 0 °C to rt, 2 h.
K
2
3
2
2
Scheme 2. Retrosynthetic Analysis of Tofacitinib (CP-690,550).
2
2

K.D. Mane, R.B. Kamble and G. Suryavanshi
Tetrahedron Letters 67 (2021) 152838
9
3% yield with 96.8% ee. The formation of compound 2a was con-
G. Ridley, H. Stadler, E. Vieira, M. Wilhelm, F.K. Winkler, W. Wostl, Chem. Biol.
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firmed by previous literature report and its optical rotation is in
well agreement with the reported value. Then the enantiopure
piperidine alcohol 2a was utilized for the synthesis of tofacitinib
as shown in the Scheme 4.
(
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using MsCl and Et
N-Methyl dezapurine 3 under basic condition to give compound 8
in 81% yield. Then N-benzyl deprotection of compound 8 was car-
3
N, followed by base mediated S
N
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ried out under hydrogenation condition using 20 wt% Pd(OH)
atm H pressure followed by in situ N-acylation using 2-cyanoa-
cetyl chloride to give (+)-tofacitinib (1) in 75% yield over two steps.
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The formation of tofacitinib (1) was confirmed by H, C NMR and
its values are in well agreement with previous reports [15].
In conclusion, the (+)-tofacitinib (1) was synthesized in 8 steps
commenced from 4-piperidinone in 22.4% overall yield with 96.8%
ee. The key steps involved are -proline catalyzed a-aminohydrox-
ylation followed by Wittig olefination and hydrogenation
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Declaration of interests
[
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B.J. Rizzuti, P.S. Sawyer, B.D. Perry, W.H. Brissette, S.P. McCurdy, E.M. Kudlacz,
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There are no conflicts to declare.
Declaration of Competing Interest
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