Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a

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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

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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.

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Organic Process Research & Development

Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a Dynamic Kinetic ResolutionReductive Amination Protocol 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 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

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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.

KEYWORDS: Asymmetric reductive amination (ARA), dynamic kinetic resolution (DKR), iridium, chiral amine

Chiral amines are important building blocks towards pharmaceuticals products. Costefficient and environmentally-friendly methods for their production are high on the wish list of the pharmaceutical industry.1 The catalytic asymmetric reductive amination (ARA)2 of substituted ketones under dynamic kinetic resolution (DKR)3 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.



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chemoselective towards the imine vs the ketone, iii. able to accommodate both E/Z isomers of the imine, iv. diastereoselective and finally v. enantioselective. Although there are quite a number of examples for the asymmetric hydrogenation-DKR of ketones towards chiral alcohols,4 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 cyclic ketones.5 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 chiral phosphoric acids.6 Kocovsky et al. prepared -amino-acids via ARA-DKR of -keto esters and nitriles using trichlorosilane as reductant.7 Rubio-Pérez et al. used asymmetric hydrogenation with chiral palladium catalysts to reduce the in situ formed imine from substituted cyclic ketones with high diastereoselectivities and enantioselectivities.8 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 lactams towards primary -amino lactams.9 Excellent diastereomeric and enantiomeric excesses were obtained using Ru-SegPhos including at a high substrate to catalyst ratio of 500.


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O R3

N

+ H2NR4 R1

R2

R3 - H 2O

R4

HN R3

R1

R4 R1

Cat*

HN +

R3

R2

R2

R4 R1

R2

Cat* N

OH R3

R3

R1

R4

HN R3

R1

R1

Cat*

R2

R2

R4

HN +

R3

R2

R4 R1

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 treatment of rheumatoid arthritis (Scheme 2).10 The (R,R)-enantiomer of chiral piperidine 1 was identified as the major cost contributor in the preparation of Tofacitinib.11 It is obtained in its enantiopure form via classical resolution. Pfizer disclosed some trials towards an enantioselective route via asymmetric hydrogenation but with limited success.12 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 O

O

O O

N 2.HCl

.

N

H N

(R)

N

(R)

N

N

N

N

N

HCl

O 3

4

N

1

CN

NH

Tofacitinib

Scheme 2. Synthetic route towards Tofacitinib via ARA-DKR 5 ACS Paragon Plus Environment


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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 we decided to focus on iridium.14 Iodine was included as additive as well since it is well-known to improve the performance of Ir catalysts in imine hydrogenation.15 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

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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 hydrogenation in a parallel reactor (Scheme 3).16 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


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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.


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H N

(R)

MeO

H N

(S)

O

(S)

(R)

N Bn

(R)

4

H N

N Bn

(R)

(S)

Ph2P

OH

(S)

Ph

L2

Fe

PCy2 N

L5 MeO MeO

L3

PPh2

No I2

O (tBu)2P

N

OMe

N Ph

Ph L10

L11

L12

Ligand Set

Solvent DCM EtOAc MeOH IPA DCM EtOAc MeOH IPA

L1

L2

L3

L4

L5

L6

L7

L8

6 4 48 41 68 32 75 76

3 4 59 35 67 28 81 77

5 9 87 83 4 58 77 72

10 6 77 35 8 6 84 65

22 69 86 79 15 23 71 42

39 42

92 82 85 83 65 64 86 88

13 18 86 69 14 25 85 85

Solvent DCM EtOAc MeOH IPA DCM EtOAc MeOH IPA

L1 100 100 78 79 69 70 80 65

L2 100 100 77 100 68 84 77 65

L3 100 100 84 97 100 80 85 90

L4 100 100 89 79 100 100 95 100

L5 29 87 90 94 100 100 85 100

alcohol 5 area % L9 L10 L11 L12 L1 11 19 9 52 0 7 14 38 41 0 88 89 80 85 17 53 75 66 71 1 6 15 5 61 0 1 16 21 27 2 85 79 77 78 7 45 58 60 68 5

L2 0 0 20 0 0 0 5 5

L3 0 0 1 0 0 1 7 2

L4 0 0 12 21 0 1 4 11

L6 L7 L8 L9 L10 L11 L12 L1 57 93 100 100 100 100 71 6 100 93 100 100 100 67 77 7 87 87 94 94 91 75 91 2 100 95 89 72 90 62 63 10 100 88 100 100 100 100 73 5 100 90 100 100 100 62 100 11 89 95 94 92 84 75 83 8 58 94 87 82 83 68 68 5

L2

L3

L4

L5

L6

L7

L8

L9 L10 L11 L12

18 15 23 13 11 11 16 23

26 14 1 16 33 18 22 17

16 0 7 11 4 11 14 0

9 12 8 9 18 12 8 3

25 30 13 10 7 12 19 14

9 21 9 15 9 6 17 12

27 36 23 4 1 6 11 13

25 23 13 20 7 27 6 19

86 65 5 11 81 43

D.e. (%)

I2

O (oTol)2P

PPh2

cis-1 area %

Additive

PPh2 L8

L7 PPh2

Trans

No I2

PCy2

Fe L6

L9

I2

L4 Ph2P

PPh2

PAr2 PAr2 Ar =

O P N O

OMe

iPr

5

N N Bn Bn (R,S)-trans-1 (S,R)-trans-1

Additive

P

PCy2

Cis H N

Fe

N

PPh2 N iPr

L1

N Ir-Ligand H2

O

PPh2 N

N N Bn Bn (R, R)-cis-1 (S,S)-cis-1

O

L5 0 0 6 0 0 0 12 7

L6 0 0 4 0 0 0 4 6

L7 0 0 5 2 1 0 6 6

L8 0 0 7 0 0 0 4 4

L9 L10 L11 L12 0 0 0 0 0 0 0 0 3 4 3 4 0 0 1 1 0 0 0 0 0 0 0 0 3 4 4 3 1 1 1 0

cis-1 E.e. (%) 3 8 17 13 14 18 18 25

4 11 13 14 10 10 14 15

15 12 24 13 12 1 15 18

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


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could be easily monitored via 1H NMR. All 1H signals of the protons of the ring (Scheme 4, A) are well resolved. After one night in deuterated MeOH in presence of tBuOK, all signals for the protons on C1 and C3 had disappeared in the 1H NMR spectrum indicated full H/D 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.


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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 towards Metolachlor,17 we felt confident Ir/bisphosphine catalysts would be active. 11 ACS Paragon Plus Environment


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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 (S,S)-1,18 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

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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.

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


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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). S/C

T

AcOH

Cis-1

d.e.

e.e.

HPLC

(mol:mol)

(°C)

(mol. eq/ 3)

(Area %)

(%)

cis-5 (%)

Yield (%)

1

50

RT

1.5

93

93

54

72

2

500

RT

1.4

68

92

60

54

3

1000

RT

1.4

54

93

65

45

4

1000

70

1

98

96

69

83

5

1000

70

0

98

96

74

85

6

1000

70

10

99

90

29

64

7

10000

70

0

96

96

76

84

#


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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) 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 H N

CH3 O MeNH2:AcOH (1.25 eq)

(R)

(R)

CH3

N

N 3

Ir/BiPheP (S:C=1000) 70°C, 50 bar H2, 18h IPA

(3R,4R)-1

(S)-BiPheP MeO MeO

PAr2 PAr2

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 preparation of a key intermediate towards Tofacitinib.19 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


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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.

ASSOCIATED CONTENT Supporting Information. Analytical methods, synthesis of the substrate, procedure for the catalyst screening. AUTHOR INFORMATION Corresponding Author [email protected] 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.


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(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,

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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. (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.



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(19) De Vries, A.; Lefort, L.; Verzijl, G. Process for preparing chiral amines, PCT WO2018/060512 A1, 05 April 2018.


Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a

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