Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a Dynamic Kinetic Resolution-Reductive Amination Protocol

Article abstract of DOI:10.1021/acs.oprd.8b00332

We report the first example of a catalytic asymmetric reductive amination under dynamic kinetic resolution (DKR) conditions for the preparation of a chiral amine as a key intermediate toward Tofacitinib, an active pharmaceutical ingredient developed by Pfizer. Such a protocol allows the preferential formation of a single product out of four possible diastereomers of the chiral amine starting from the corresponding racemic ketone. The chiral iridium catalyst able to perform such a feast was discovered through a mix of high-throughput screening, racemization study, and reaction optimization.

Full text of DOI:10.1021/acs.oprd.8b00332

Subscriber access provided by University of Winnipeg Library
Full Paper
Asymmetric Synthesis of a Key Intermediate for Tofacitinib via
a Dynamic Kinetic Resolution-Reductive Amination Protocol
Gerard Verzijl, Christian Schuster, Thomas Dax, Andre de Vries, and Laurent Lefort
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00332 • Publication Date (Web): 14 Nov 2018
Downloaded from http://pubs.acs.org on November 14, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Asymmetric Synthesis of a Key Intermediate for
Tofacitinib via a Dynamic Kinetic Resolution-
Reductive Amination Protocol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Gerard K.M. Verzijla, Christian Schusterb, Thomas Daxb, André H.M. de Vriesa and Laurent
Leforta, *
a InnoSyn B.V., Urmonderbaan 22, 6167 RD Geleen, The Netherlands
b Patheon Austria GmbH, Sankt-Peter Straße 25, A-4020 Linz, Austria
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 22
1
2
3
4
TOC:
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
ACS Paragon Plus Environment

Page 3 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT: Herein, we report the first example of a catalytic asymmetric reductive amination
under dynamic kinetic resolution (DKR) conditions for the preparation of a chiral amine as a
key intermediate towards Tofacitinib, an active pharmaceutical ingredient developed by
Pfizer. Such a protocol allows the preferential formation of a single product out of 4 possible
diastereomers of the chiral amine starting from the corresponding racemic ketone. The chiral
iridium catalyst able to perform such a feast was discovered through a mix of high throughput
screening, racemization study and reaction optimization.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS: Asymmetric reductive amination (ARA), dynamic kinetic resolution (DKR),
iridium, chiral amine
Chiral amines are important building blocks towards pharmaceuticals products. Cost-
efficient and environmentally-friendly methods for their production are high on the wish list
1
2
of the pharmaceutical industry. The catalytic asymmetric reductive amination (ARA) of -
3
substituted ketones under dynamic kinetic resolution (DKR) would fulfill such requirements
(Scheme 1). Indeed, starting from a racemic -substituted ketone, a single chiral amine out of
four possible stereoisomers is formed via instalment of two adjacent stereogenic centers in one
step. The catalyst able to perform such a remarkable transformation has to exhibit a range of
features: it should be i. active under reductive amination and racemization conditions, ii.
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 22
1
2
3
4
5
6
chemoselective towards the imine vs the ketone, iii. able to accommodate both E/Z isomers of
the imine, iv. diastereoselective and finally v. enantioselective.
7
8
9
Although there are quite a number of examples for the asymmetric hydrogenation-DKR of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
ketones towards chiral alcohols, much less is known in the field of ARA via DKR towards
chiral amines. Lasaletta et al. were the first to report this transformation for -substituted
5
cyclic ketones. The reduction was achieved via transfer hydrogenation using the Noyori
catalyst and Et3N-HCOOH as reducing agent. List et al. developed a similar procedure for
aldehydes and ketones based on organocatalysts using a combination of Hantzsch ester and
6
chiral phosphoric acids. Kocovsky et al. prepared -amino-acids via ARA-DKR of -keto
7
esters and nitriles using trichlorosilane as reductant. Rubio-Pérez et al. used asymmetric
hydrogenation with chiral palladium catalysts to reduce the in situ formed imine from -
8
substituted cyclic ketones with high diastereoselectivities and enantioselectivities. All these
protocols, however, are arguably not directly applicable for production at scale due to their
high catalyst loadings and/or relative high cost reducing agents, and/or the use of protective
groups and/or long reaction times. During the completion of this manuscript, Zhang et al.
reported a very efficient DKR via ARA of a particular class of ketones, i.e. racemic -keto
9
lactams towards primary -amino lactams. Excellent diastereomeric and enantiomeric
excesses were obtained using Ru-SegPhos including at a high substrate to catalyst ratio of 500.
4
ACS Paragon Plus Environment

Page 5 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
R4
R1
R4
R1
R4
HN
HN
O
N
N
+ H2NR4
- H2O
R3
R3
+
+
R3
R3
R1
R1
Cat*
Cat*
R2
R2
R2
R2
Cat*
OH
R1
R4
R4
R1
R4
R1
HN
HN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R3
R3
R3
R3
R1
R2
R2
R2
R2
Scheme 1. Asymmetric reductive amination of a -substituted ketone coupled with dynamic
kinetic resolution.
Tofacitinib (trade names Xeljanz and Jakvinus) is a drug developed by Pfizer for the
10
treatment of rheumatoid arthritis (Scheme 2). The (R,R)-enantiomer of chiral piperidine 1
11
was identified as the major cost contributor in the preparation of Tofacitinib. It is obtained
in its enantiopure form via classical resolution. Pfizer disclosed some trials towards an
12
enantioselective route via asymmetric hydrogenation but with limited success. We
envisioned that a synthetic procedure based on ARA via DKR would allow the preparation of
the enantiopure key intermediate 1. Here we describe our successful search for a homogeneous
hydrogenation catalyst able to perform this transformation and therefore the first application
of this technology to a relevant pharmaceutical intermediate.
ARA-DKR
H
(R)
O
O
O
N
N
N
N
(R)
O
N
N
N
N
N
.HCl
N
NH
O
CN
2.
Tofacitinib
HCl
3
1
4
Scheme 2. Synthetic route towards Tofacitinib via ARA-DKR
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 22
1
2
3
4
5
6
7
8
9
The starting ketone 3 was prepared from the commercially available -ketoester 2 via
alkylation with MeI followed by decarboxylation (See supplementary information). During
the reductive amination, alcohols can be formed by reduction of the ketone. Their formation
can be avoided if the catalyst is selectively reducing the imine or if no ketone is present due to
a very fast formation of the imine. Therefore we first investigated the formation of Me imine
4 with the goal to find conditions where it would occur quickly. In presence of 10 eq of MeNH2
(from a commercial 33 wt% solution in EtOH), ketone 3 is converted into imine 4 with a GC
yield above 97% when the reaction is run in IPA at 50°C during 17h. When the reaction is run
neat, almost full conversion is obtained within 2h at 50°C and 5h at room temperature.
Remarkably, no removal of water produced during the reaction was needed. The latter
procedure (neat, room temperature) was used to prepare imine 4 for subsequent studies.
With substrate 4 in hand, we initiated a broad screening for an enantioselective
hydrogenation catalyst. At this stage, we were solely concerned with finding an active catalyst.
No particular effort was made to fine-tune the reaction conditions in order to promote the
epimerization of stereogenic center (required for DKR). Due to the numerous literature
precedents13a and our own experience in the field of enantioselective imine hydrogenation,13b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14
we decided to focus on iridium. Iodine was included as additive as well since it is well-known
15
to improve the performance of Ir catalysts in imine hydrogenation. Using our parallel reactor
where up to 96 hydrogenation can be carried out in parallel, we tested 12 chiral ligands in 4
different solvents with or without iodine. The chiral ligands of the initial set were chosen from
6
ACS Paragon Plus Environment

Page 7 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
various classes of phosphorus based ligands all of them being reported as efficient in imine
hydrogenation. The combination of all variables (ligands, additives, solvents) generated a total
of 96 catalytic mixtures that were prepared using a liquid handling robot and submitted to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16
hydrogenation in a parallel reactor (Scheme 3). The color coded tables in Scheme 3 (with red
= high, blue = low) shows that the desired amine 1 is obtained in high yields with many
catalytic systems. Small amounts of alcohol 5 are observed in MeOH and IPA due to the
residual water present in these solvents that leads to the hydrolysis of 4 back to 3 followed by
hydrogenation. In many cases, a very high diastereomeric excess is observed in favor of the cis
compound – i.e. the one required for Tofacitinib – as expected for an approach of the catalyst
trans to the methyl group. Enantiomeric excesses were overall low with a maximum value of
36%. For the catalysts exhibiting low conversion (i.e. below 50%, therefore in kinetic
resolution mode), no significant preference for the S- or R-enantiomers of 4 was observed.
Equally, for those close to full conversion, the low enantiomeric excesses indicates that very
little to no racemization of the stereocenter in imine 4 or ketone 3 took place. Nevertheless,
the high number of catalysts giving high conversion confirmed that focusing on catalysts based
on Ir and chiral phosphines was the right way forward.
The next step was to search for conditions to promote racemization of the stereocenter in
the prochiral substrate, i.e. a prerequisite to a DKR process. We anticipated that a strong base
could fulfill this purpose. Therefore, tBuOK was added to the mixture of catalyst and imine
substrate 4 in IPA prior to the next hydrogenation test. The same 12 Ir catalysts were tested
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 22
1
2
3
4
5
6
7
8
9
with and without iodine under the same hydrogenation conditions. Unfortunately, for almost
all catalysts, a very low yield of the desired amine was observed indicating a strong catalyst
deactivation by tBuOK (See Supplementary Info). In the few cases where a significant amount
of cis-amine 1 was formed, no increase of ee was observed compared to the case where no base
was added. Most probably, the chiral catalyst decomposed under basic conditions into an
achiral Ir species with some residual hydrogenation activity. We therefore decided to study in
more detail the epimerization using ketone 3 as a substrate since it was more easier to handle
than the hydrolysis-prone imine 4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment

Page 9 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
MeO
H
N
H
(S)
(R)
N
O
P
O
O
(S)
O
O
(R)
P
OMe
PPh2
N
Fe
N
PPh2
N
PPh2
N
N
N
iPr
Bn
iPr
Ph
PCy2
Bn
L1
L2
L3
L4
9
1
1
(R, R)-cis- (S,S)-cis-
Ph2P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
Ph2P
OH
PCy2
PCy2
Fe
Cis
Fe
N
Ir-Ligand
H2
PPh2
PPh2
L8
N
H
H
(S)
N
(R)
Bn
L5
L6
N
N
L7
Bn
(R)
(S)
4
5
PPh2
PPh2
O
O
MeO
MeO
PAr2
PAr2
N
N
(tBu)2P
N
(oTol)2P
N
Bn
Bn
Ar =
OMe
Ph
L12
Ph
L11
1
1
(R,S)-trans- (S,R)-trans-
L10
L9
Trans
Ligand Set
cis-1 area %
alcohol 5 area %
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12 L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12
Additive
Solvent
DCM
EtOAc
MeOH
IPA
DCM
EtOAc
MeOH
IPA
0
0
0
0
0
0
1
0
0
1
7
2
0
0
0
0
0
0
4
0
0
0
4
6
0
0
5
2
1
0
6
6
0
0
7
0
0
0
4
4
0
0
3
0
0
0
3
1
0
0
4
0
0
0
4
1
0
0
3
1
0
0
4
1
0
0
4
1
0
0
3
0
6
4
3
4
5
9
10 22 39 92 13 11 19
9
52
42
6
69
82 18
7
14 38 41
I2
17 20
12
21
0
6
48 59 87 77 86 86 85 86 88 89 80 85
41 35 83 35 79 65 83 69 53 75 66 71
1
0
1
7
5
0
0
0
5
5
0
0
68 67
4
8
6
15
5
65 14
6
15
5
61
2
1
0
32 28 58
23 11 64 25 16 21 27
No I2
4
12
7
75 81 77 84 71 81 86 85 85 79 77 78
76 77 72 65 42 43 88 85 45 58 60 68
11
D.e. (%)
cis-1 E.e. (%)
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12 L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12
Additive
Solvent
DCM
EtOAc
MeOH
IPA
DCM
EtOAc
MeOH
IPA
100 100 100 100 29 57 93 100 100 100 100 71
100 100 100 100 87 100 93 100 100 100 67 77
78 77 84 89 90 87 87 94 94 91 75 91
79 100 97 79 94 100 95 89 72 90 62 63
69 68 100 100 100 100 88 100 100 100 100 73
70 84 80 100 100 100 90 100 100 100 62 100
80 77 85 95 85 89 95 94 92 84 75 83
65 65 90 100 100 58 94 87 82 83 68 68
6
7
2
18 26 16
9
25
9
27 25
3
8
4
15
15 14
23
0
7
12 30 21 36 23
11 12
I2
1
8
9
13
9
23 13 17 13 24
10 13 16 11
11 33
10 15
4
1
6
20 13 14 13
14 10 12
27 18 10
18 14 15
14 12 13 19 25 15 18
5
4
18
7
9
6
7
11 11 18 11 12 12
1
No I2
8
5
16 22 14
23 17
8
3
19 17 11
6
0
Scheme 3. Results of the first catalyst screening for the asymmetric hydrogenation of imine 4.
(Conditions: Ir (0.001mmol), I2 (none or 0.002mmol), substrate 4 (0.05mmol), solvent = 1mL,
50 bar H2, R.T., 18h. D.e. is the diastereomeric excess for the cis isomer; E.e.’s are reported in
absolute value.)
Due to the non-availability of the enantiopure ketone 3, the epimerization was indirectly
studied via the H/D exchange reaction of the proton at the stereocenter. Such a transformation
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 22
1
2
3
4
could be easily monitored via 1H NMR. All 1H signals of the protons of the ring (Scheme 4, A)
5
6
7
are well resolved. After one night in deuterated MeOH in presence of tBuOK, all signals for
8
9
1
the protons on C1 and C3 had disappeared in the H NMR spectrum indicated full H/D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
exchange and therefore epimerization at the C3 stereocenter (Scheme 4, B). In agreement, the
signal of the methyl group on C3 also became a (1:1:1) triplet with a very small coupling
constant J(D-CH3)). Since an alkoxide base was not suited for our AH-DKR approach, we
investigated whether epimerization could take place under acidic conditions via keto-enol
tautomerization. With 4 equivalent of CD3COOD relative to 3 (0.05M in CD3OD), we were
pleased to observe also a significant decrease of the signal of the proton on C3 from 18% after
5 min at room temperate, to 60% in 4h and 100% overnight. The rate of epimerization was
about 3 times slower when only 1 equivalent of acid was used (see Supplementary info). A
similar set of experiments was performed with imine 4 but in this case, the NMR spectra were
much more difficult to analyze due to the formation of the ketone 3 via hydrolysis and the
overlaps of numerous signals. However, the disappearance of some key NMR signals was also
observed showing that epimerization of the imine 4 also occurs in presence of acetic acid.
10
ACS Paragon Plus Environment

Page 11 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. 1H NMR of 3 (Spectrum A) and 3 treated overnight with tBuOK (Spectrum B) in
CD3OD.
Considering that both ketone 3 and imine 4 can epimerize under acidic conditions, we
needed to verify next that the imine 4 could be formed in presence of acetic acid. Ketone 3
was reacted in different solvents (DCM, EtOAc, CD3OD, IPA) with the acetate salt of MeNH2
(4 equivalents relative to 3) at room temperature. For all solvents, a significant amount of imine
was formed overnight – without the need to remove the water generated during the reaction.
Even as an acetate salt, MeNH2 was reactive enough.
At this stage, the last missing piece of the puzzle of the envisaged ARA-DKR protocol was
the asymmetric hydrogenation catalyst. It had to operate efficiently under the newly identified
acidic conditions for the imine formation/epimerization. Considering the fact that acetic acid
was used as an additive in the well-known Ir catalyzed asymmetric hydrogenation of the imine
17
towards Metolachlor, we felt confident Ir/bisphosphine catalysts would be active.
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 22
1
2
3
4
5
6
7
8
9
Additionally, Zhang et al. demonstrated that acetic acid was in fact key to improve the catalyst
activity in their related ARA-DKR protocol of -keto lactams.9 The same library of Ir catalysts
under the same conditions (12 catalysts, 4 solvents, with and without iodine, See Scheme 3)
was therefore tested using ketone 3 as substrate with 4 equivalent of the acetate salt of MeNH2.
Additional acetic acid was added to promote the racemization of the ketone 3 and/or imine 4
(40 eq/substrate in aprotic solvents DCM and EtOAc; 1.5 eq/substrate in MeOH and IPA).
Using our high throughput reactor, the 96 hydrogenation reactions were conducted in parallel
during 18h at room temperature. For most of the catalysts/solvent combination (Scheme 5),
high yields of cis-amine 1 were obtained demonstrating that many catalysts were active under
acidic conditions achieving the direct conversion from ketone 3 into the desired amine
without isolation of the imine 4 – i.e. truly an asymmetric reductive amination process. The
formation of alcohol 5 was overall very limited despite the fact that formed water was not
removed. As already observed, the cis-amine was largely favored over the trans. Gratifyingly,
the ee’s obtained for this run were higher than in our first attempt confirming that the
reductive amination occurred under DKR conditions. The most enantioselective catalyst based
on ligand L9 (in IPA as a solvent and in absence of iodine) gives an assay yield of 71% of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18
(S,S)-1, i.e. significantly higher than the theoretical maximum of 50% without epimerization.
The best ligands in term of ee’s were BiPheP (L9), a bidentate phosphine with axial chirality,
two ligands from the Solvias collection, i.e. a Naud ligand (L3) with an oxazoline moiety and
TaniaPhos (L6), and NorPhos (L10) (with ee’s of 64%, 47%, 32%, and 30% respectively). In an
12
ACS Paragon Plus Environment

Page 13 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
attempt to further improve the enantiomeric excess, 48 new chiral ligands were tested in IPA
with and without iodine (See Supplementary Information). A bulky SegPhos, DTBM-SegPhos
gave very similar results as BiPheP while none of the other newly tested ligands appeared to
outperform BiPheP.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Results of the second catalyst screening for the reductive amination of ketone 3
under DKR conditions. (Conditions: Ir (0.001mmol), I2 (none or 0.002mmol), 3 (0.05mmol),
MeNH3.OAc (4 eq/3), CH3COOH (1.5 or 40 eq/3), solvent = 1mL, 50 bar H2, R.T., 18h; The
best results in terms of enantiomeric excess are circled in blue.)
Further optimization was therefore carried out using the Ir/BiPheP catalyst focusing on
improving the substrate to catalyst ratio (S/C) and the enantioselectivity (see Table 1).
Increasing S/C from 50 to 1000 mol:mol lead to a significant increase of enantiomeric excess.
At a higher S/C, converting all the substrate took considerably longer, hence leaving more time
13
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 22
1
2
3
4
5
6
7
8
9
for the epimerization to occur. At room temperature the overall HPLC yield of the single
diastereomer remained rather low (Entries 1-3). However, by increasing the temperature to
70°C, full conversion of 3 into the desired amine 1 was obtained with the same catalyst loading
(Entry 4). Notably, even a slight increase of d.e. and e.e. was observed at such an elevated
temperature – consistent with an acceleration of the epimerization reaction. Moreover,
additional acetic acid was no longer needed at this temperature for the epimerization to occur
(Entry 5). In fact, a large excess of acetic acid appeared to be detrimental to the enantiomeric
excess (Entry 6). Lowering even further the catalyst loading was possible. At a remarkably high
substrate to catalyst ratio of 10,000, a yield of a single diastereomer (i.e. 84% assay yield) was
obtained indicating that the catalyst was sufficiently active and robust for a cost-effective
implementation at scale (Entry 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
S/C
T
AcOH
Cis-1
d.e.
(%)
93
e.e.
cis-5 (%)
54
HPLC
Yield (%)
72
#
1
2
3
4
5
6
7
(mol:mol) (°C) (mol. eq/ 3) (Area %)
50
RT
RT
RT
70
1.5
1.4
1.4
1
93
68
54
98
98
99
96
500
92
93
96
96
90
96
60
65
69
74
29
76
54
45
83
85
64
84
1000
1000
1000
1000
10000
70
0
70
10
0
70
14
ACS Paragon Plus Environment

Page 15 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Table 1. Optimization of Ir/BiPheP catalyst. (Conditions: Ir/BiPheP (0.001-5.10-6 mmol), 3
(0.05mmol), MeNH3.OAc (4 eq/3), CH3COOH (0-10 eq/3), solvent = 1mL, 50 bar H2, R.T.-
70°C, 18h. E.e. for (S,S)-cis-1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Finally, we applied our ARA/DKR protocol on a preparative scale using the optimized
conditions using the right hand of the chiral ligand, i.e. (S)-BiPheP (See Supplementary
Information). Ketone 3 was fully converted to the desired (R,R)-amine with 72 % e.e. and 95
% d.e. The product 1 was isolated in 86 % yield as its bis-HCl-salt with a chemical purity of 97
% (Scheme 6).
CH3
CH3
H
N
(S)-BiPheP
O
CH3
(R)
(R)
MeNH2:AcOH (1.25 eq)
MeO
MeO
PAr2
PAr2
N
N
Ir/BiPheP (S:C=1000)
70°C, 50 bar H2, 18h
IPA
3
1
(3R,4R)-
Ar = 3,5,-di-tBu, 4-OMe
Isolated yield = 86% as bis-HCl salt
Purity (HPLC) = 97%
Scheme 6. ARA-DKR under optimized conditions.
In conclusion, we have developed an efficient protocol based on ARA and DKR for the
19
preparation of a key intermediate towards Tofacitinib. Remarkably, the counterintuitive use
of acidic conditions for the imine synthesis and the racemization provided the breakthrough
towards such a protocol. High throughput experimentation was key to identify a catalyst based
on Ir and BiPheP as a chiral ligand that appeared to be active at loadings compatible to the
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 22
1
2
3
4
5
6
7
8
9
severe cost requirement imposed on industrial manufacturing. We expect that our
methodology could be applied to other substrates and therefore allow the efficient access to
other important chiral amines.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information. Analytical methods, synthesis of the substrate, procedure for the
catalyst screening.
AUTHOR INFORMATION
Corresponding Author
Laurent.lefort@innosyn.com
Present Addresses
Author Contributions
The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
ACKNOWLEDGMENT
We thank our colleague Math Boesten from the analytical group for his invaluable support in
HPLC method development.
16
ACS Paragon Plus Environment

Page 17 of 22
Organic Process Research & Development
1
2
3
4
REFERENCES
5
6
7
8
9
(1) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer Jr., J.R.; Linderman,
R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaksh, A.; Zhang, T. Y. Key green
chemistry research areas—a perspective from pharmaceutical manufacturers, Green Chem.
2007, 9, 411-420.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) (a) Wang, C.; Xiao, J. Asymmetric Reductive Amination, Top. Curr. Chem. 2014, 343,
261-282. (b) Nugent, T. C.; El-Shazly, M. Chiral Amine Synthesis – Recent Developments and
Trends for Enamide Reduction, Reductive Amination, and Imine Reduction, Adv. Synth.
Catal. 2010, 352, 753-819.
(3) (a) Kagan H. B.; Fiaud J. C. Kinetic Resolution In Topics in Stereochemistry; Eliel E. L.,
Wilen S. H. Eds.; John Wiley & Sons, Inc., Hoboken, NJ, USA, 1988, 18, 249-330. (b) Nakano
K.; Kitamura M. Dynamic Kinetic Resolution (DKR) In Separation Of Enantiomers : Synthetic
Methods; Todd M. Eds; Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim; 2014, 161-215.
(c) Pellissier, H. Recent developments in dynamic kinetic resolution, Tetrahedron 2011, 67,
21, 3769-3802.
(4) (a) Xie, J.-H.; Zhou, Q.-L. Catalytic Asymmetric Hydrogenation of -Substituted Ketones
and Aldehydes via Dynamic Kinetic Resolution: Efficient Approach to Chiral Alcohols,
Aldrichimica Acta, 2015, 48, 2, 33-40. (b) Echeverria, P-G.; Ayad, T.; Phansavath, P.;
Ratovelomanana-Vidal, V. Recent Developments in Asymmetric Hydrogenation and Transfer
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 22
1
2
3
4
5
6
7
8
Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution, Synthesis 2016,
48(16), 2523-2539. (c) Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Transition-Metal-Mediated
Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric
Transformations, Chem. Rev. 2017, 117, 4528-4561.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) Ros, A.; Magriz, A.; Dietrich, H.; Ford, M.; Fernandez, R.; Lassaletta, J. M. Transfer
Hydrogenation of -Branched Ketimines: Enantioselective Synthesis of Cycloalkylamines via
Dynamic Kinetic Resolution, Adv. Synth. Catal. 2005, 347, 1917-1920.
(6) (a) Hoffmann, S.; Nicoletti, M.; List, B. Catalytic Asymmetric Reductive Amination of
Aldehydes via Dynamic Kinetic Resolution, J. Am. Chem. Soc. 2006, 128, 13074-13075. (b)
Wakchaure, V. J.; Zhou, J.; Hoffmann, S.; List, B. Catalytic Asymmetric Reductive Amination
of -Branched Ketones, Ang. Chem. Int. Ed. 2010, 49, 4612-4614. (c) Zhou, J.; List, B. Synthesis
of trans-3-Substituted Cyclohexylamines via Brønsted Acid Catalyzed and Substrate-Mediated
Triple Organocatalytic Cascade Reaction, Synlett 2007, 2037-2040.
(7) Malkov, A. V.; Stoncius, S.; Vranková, K.; Arndt, M.; Kocovsky, P. Dynamic Kinetic
Resolution in the Asymmetric Synthesis of -Amino Acids by Organocatalytic Reduction of
Enamines with Trichlorosilane, Chem. Eur. J. 2008, 14, 8082-8085.
18
ACS Paragon Plus Environment

Page 19 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
(8) Cabrera, A.; Sharma, P.; Pérez-Flores, F. J.; Velasco, L.; Arias, J. L.; Rubio-Pérez, L.
Diastereo- and enantioselective reductive amination of cycloaliphatic ketones by preformed
chiral palladium complexes, Catal. Sci. Technol. 2014, 4, 2626-2630.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Lou, Y.; Hu, Y; Lu, J.; Guan, F.; Gong, G.; Yin, Q.; Zhang, X. Dynamic Kinetic Asymmetric
Reductive Amination: Synthesis of Chiral Primary β‐Amino Lactams, Angew. Chem. Int. Ed.
2018, 57, 14193-14197.
(10) (a) Tofacitinib, Drugs R D 2010, 10, 4, 271-284. (b) Garber, K. Pfizer’s first-in-class JAK
inhibitor pricey for rheumatoid arthritis market, Nature Biotechnology 2013, 31, 1, 3-4.
(11) (a) Patil, Y. S.; Bonde, N. L.; Kekan, A. S.; Sathe, D. G.; Das, A. An Improved and Efficient
Process for the Preparation of Tofacitinib Citrate, Org. Process Res. Dev. 2014, 18, 1714-1720.
(b) Wilcox, G. E.; Koecher, C.; Vries, T.; Flanagan, M. E.; Munchhof, M. J. Optical resolution
of (1-benzyl-4-methylpiperidin-3-yl) methylamine and the use thereof for the preparation of
pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors, PCT WO 02096909, 5
December 2002. (c) Brown Ripin, D. H.; Abele, S.; Cai, W.; Blumenkopf, T.; Casavant, J. M.;
Doty, J. L.; Flanagan, M.; Koecher, C.; Laue, K. W.; McCarthy, K.; Meltz, C.; Munchhoff, M.;
Pouwer, K.; Shah, B.; Sun, J.; Teixeira, J.; Vries, T.; Whipple, D. A.; Wilcox, G. Development
of a Scaleable Route for the Production of cis-N-Benzyl-3-methylamino-4-methylpiperidine,
Org. Process Res. Dev. 2003, 7, 115-120. (d) Cai, W.; Colony, J. L.; Frost, H.; Hudspeth, J. P.;
19
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 22
1
2
3
4
5
6
7
8
Kendall, P. M.; Krishnan, A. M.; Makowski, T.; Mazur, D. J.; Phillips, J.; Brown Ripin, D. H.;
Ruggeri, S. G.; Stearns, J. F.; White, T. D. Investigation of Practical Routes for the Kilogram-
Scale Production of -3-Methylamino-4-methylpiperidines, Org. Process Res. Dev. 2005, 9, 51-
56. (e) Carvalho, L.; Lourenço, A.; Ferreira, L.; Branco, P. Tofacitinib synthesis ‐ an asymmetric
challenge, Eur. J. Org. Chem. 2018, Accepted Author Manuscript.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) Ruggeri, S. G.; Hawkins, J. M.; Makowski, T. M.; Rutherford, J. L.; Urban, F. J.
Pyrrolo[2,3-d]Pyrimidine Derivatives; Their Intermediates and Synthesis, PCT WO
2007012953, 1 February 2007.
(13) (a) Spindler, F.; Blaser, H.-U. Enantioselective Hydrogenation of C=N Functions and
Enamines, In The Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J.
Eds; Wiley-VCH Verlag GmbH, Weinheim, Germany; 2006, 1193-1214. (b) Verzijl, G. K. M.;
de Vries, A. H. M.; de Vries, J. G.; Kapitan, P.; Dax, T.; Helms, M.; Nazir, Z.; Skranc, W.;
Imboden, C.; Stichler, J.; Ward, R. A.; Abele, S.; Lefort, L. Catalytic Asymmetric Reduction of
a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or
Transfer Hydrogenation?, Org. Process Res. Dev. 2013, 17, 1531-1539.
(14) Our work was performed in 2015 before the disclosure of two efficient Ru catalysts for
the ARA of ketones: (a) Gallardo-Donaire, J; Hermsen, M.; Wysocki, J; Ernst, M; Rominger,
F.; Trapp, O.; Hashmi, A. S. K.; Schäfer, A.; Comba, P.; Schaub, T. Direct Asymmetric
Ruthenium-Catalyzed Reductive Amination of Alkyl–Aryl Ketones with Ammonia and
20
ACS Paragon Plus Environment

Page 21 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
Hydrogen, J. Am. Chem. Soc. 2018, 140, 355-361. (b) Tan, X.; Gao, S.; Zeng, W.; Xin, S.; Zhang,
X. Asymmetric Synthesis of Chiral Primary Amines by Ruthenium- Catalyzed Direct
Reductive Amination of Alkyl Aryl Ketones with Ammonium Salts and Molecular H2, J. Am.
Chem. Soc. 2018, 140, 2024-2027.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) The positive role of I2 in Ir-catalyzed hydrogenation was first identified in 1990. See:
Chan, Y. N. C.; Osborn, J. A. Iridium(III) hydride complexes for the catalytic enantioselective
hydrogenation of imines, J. Am. Chem. Soc. 1990, 112, 9400-9401.
(16) Robotic equipment: Zinsser Lissy liquid handling robot placed inside a glovebox, see
http://www.zinsserna.com/tools_liquidhandling.htm. Parallel hydrogenation autoclave:
Premex A96 reactor, see http://www.premex-reactorag.ch/index.php?page=464 (accessed July
27, 2018).
(17) Blaser, H. U.; Buser, H. P.; Coers, K.; Hanreich, R.; Jalett, H. P.; Jelsch, E.; Pugin, B.;
Schneider, H. D.; Spindler, F.; Wegmann, A. The Chiral Switch of Metolachlor: The
Development of a Large-Scale Enantioselective Catalytic Process, Chimia 1999, 53, 275-280.
(18) The screening and the optimization was conducted with (R)-BiPheP since it was
available in our ligand library leading to the formation of the undesired (S,S)-diastereomer for
Tofacitinib. However, the (R,R)-diastereomer can be obtained via the use of (S)-BiPheP.
21
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 22
1
2
3
4
5
6
(19) De Vries, A.; Lefort, L.; Verzijl, G. Process for preparing chiral amines, PCT
7
8
9
WO2018/060512 A1, 05 April 2018.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22
ACS Paragon Plus Environment