Asymmetric Fluorination Approach to the Scalable Synthesis of a SYK Inhibitor

Article abstract of DOI:10.1021/acs.oprd.5b00131

A large-scale process for the synthesis of SYK inhibitor 1 has been developed and used to deliver multi-kilogram yields of this active pharmaceutical ingredient. Integral to the scalable process is a combined chiral auxiliary and chiral catalyst mediated

Full text of DOI:10.1021/acs.oprd.5b00131

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Full Paper
Asymmetric Fluorination Approach to
the Scalable Synthesis of a SYK Inhibitor
Neil R Curtis, Suzanne Davies, Matthew Gray, Stuart Grahame
Leach, Ross A. McKie, Lois E. Vernon, and Andrew Walkington
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 15 Jun 2015
Downloaded from http://pubs.acs.org on June 15, 2015
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Asymmetric Fluorination Approach to the Scalable
Synthesis of a SYK Inhibitor
Neil R. Curtis, Suzanne H. Davies, Matthew Gray,* Stuart G. Leach,* Ross A. McKie, Lois E. Vernon†
and Andrew J. Walkington
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Product Development, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire, SG1 2NY, UK
* Matthew.2.Gray@gsk.com; Stuart.G.Leach@gsk.com
† Deceased
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TABLE OF CONTENTS GRAPHIC
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ABSTRACT
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A large scale process for the synthesis of SYK inhibitor 1 has been developed and used to deliver multiꢀ
kilos of API. Integral to the scalable process is a combined chiral auxiliary and chiral catalyst mediated
diastereoselective fluorination to provide 14. Safe processes for BH3·DMS mediated reduction of ester
and amide functions and azide introduction, and a robust SuzukiꢀMiyaura coupling of pyrazyl boronate
10 with chloronapthyridine 9 are described.
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KEYWORDS
Fluorination, Asymmetric, Borane, Safety, Scalable, Suzuki
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INTRODUCTION
7ꢀ[1ꢀ(1,1ꢀDimethylethyl)ꢀ1Hꢀpyrazolꢀ4ꢀyl]ꢀNꢀ{[(3S)ꢀ3ꢀfluoroꢀ3ꢀpiperidinyl]methyl}ꢀ1,6ꢀ
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naphthyridinꢀ5ꢀamine 11 is a potent and selective inhibitor of spleen tyrosine kinase (SYK),2 a nonꢀ
receptor kinase implicated in the mediation of diverse cellular responses, including proliferation,
differentiation and phagocytosis. As such, SYK inhibitors may have application in a number of
therapeutic areas, including rheumatoid arthritis,3 Bꢀcell lymphoma4 and asthma/rhinitis.5 To support
preꢀclinical and clinical evaluation, the project required rapid preparation of multiꢀhundred gram
quantities of 1, shortly followed by supply of multiꢀkilo quantities. Herein we describe the development
of a synthetic route to allow operation on multiꢀkilo scale, along with a discussion of salient issues
relating to the safe operation thereof.
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The medicinal chemistry route was used to prepare multiꢀgram quantities of 1 (Scheme 1). However,
a number of issues were identified which would need to be addressed prior to further scaleꢀup. The use
of a poorly enantioselective fluorination reaction with Nꢀfluorobenzenesulfonimide (NFSI)6 necessitated
chiral HPLC purification, and inherently unsafe procedures using borane, sodium azide and TFA
respectively would all need to be circumvented.
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Scheme 1.a Medicinal Chemistry Route to 1.
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O
O
O
O
F
F
F
c
5
6
NBoc
b
a
TfO
HO
NBoc
EtO
NH
EtO
NH
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N
N
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d
Cl
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F
O
O
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HN
NH
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Cl
H2N
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HN
NBoc
N
e
10
8
NBoc
NBoc
N3
N
g
f
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Cl
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aReagent and conditions: (a) (i) (S)ꢀBINAPꢀPd(OTf)2(H2O)2, 2,6ꢀlutidine, NFSI, EtOH, 0 °C, 18 h; (ii)
chiral HPLC, 50%, >99% ee; (b) (i) BH3·THF (1 M in THF), THF, reflux, 24 h; (ii) Boc2O, NEt3,
CH2Cl2, 20 °C, 3 h, 86%; (c) Tf2O, NEt3, DCM, −10 °C, quant.; (d) NaN3, DMF, 80 °C, 1 h, quant.; (e)
H2 (atmospheric), Pd/C, EtOH, 20 °C, 18 h, quant.; (f) DIPEA, NMP, 130 °C, 16 h, 86%; (g) (i)
Pd(PPh3)4, Cs2CO3, 5:1 dioxane/water, µW, 130 °C, 2 h; (ii) TFA, CH2Cl2, 20 °C, 20 min, 57%.
RESULTS AND DISCUSSION
Development of the Asymmetric Fluorination. The medicinal chemistry preparation of 3 (Scheme 1)
gave a modest 44% ee in favour of the required enantiomer, and required flash column chromatography
followed by lengthy chiral HPLC to upgrade the ee to >99%, giving enantiomerically pure 3 in 50%
yield. While this method could theoretically be used for the initial scaleꢀup campaign, the time, cost and
solvent waste associated with this approach made it attractive to explore alternatives, especially as this
would be impracticable for further scaleꢀup. A survey of recent literature7 indicated that the current
conditions represented stateꢀofꢀtheꢀart for 1,3ꢀdicarbonyls, although there might be scope for improved
enantioselectivity using bulkier palladium ligands (such as xylylꢀBINAP, DMꢀSEGPHOS or DTBMꢀ
SEGPHOS).8 Reactions using these bulkier ligands gave improved enantioselectivities (Scheme 2,
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Table 1), although reducing the catalyst loading from 5 mol% to 1 mol% caused a significant drop in ee
(entries 5 and 6), presumably due to competing background racemic reaction. Unsubstituted BINAP
catalyst was more tolerant to reduction in loading (entries 1 and 7). Considering the high cost of these
ligands in combination with the need for extensive optimisation to achieve useful ee’s (>98%),
alternative solutions were sought. One possibility was replacement of the ethyl ester with a bulkier ester.
This was investigated using the tꢀbutyl ester, giving some improvement in ee (entry 8). However, even
in combination with xylylꢀBINAP, 87% ee was some way off an acceptable level (entry 9). It was
rationalised that a bulky chiral ester might confer favourable chiral influence, in combination with the
matched chiral catalyst to allow higher selectivity through the formation of diastereoisomers. Menthol
was an ideal candidate, since it is a low cost chiral secondary alcohol, with significant steric bulk. The
(–)ꢀmenthyl ester was initially used with both enantiomers of the catalyst, with (S)ꢀBINAP indicating a
mismatched case due to poor diastereoselectivity (entries 10 and 12). Gratifyingly, the matched example
using (R)ꢀBINAP gave 99% de with 5 mol% loading at 20 ºC (entry 11), while reaction at ꢀ10 ºC gave
only 91% de (entry 13). It was also possible to drop the catalyst loading to 1% while still achieving 94%
de (entry 15). This was a synthetically useful compromise due to purging of the minor diastereoisomer
by crystallisation (100% de).9 It should be noted that crystallisation did not enhance the ee of the ethyl
or tꢀbutyl esters.
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Scheme 2.a Screen of Asymmetric Fluorination Reaction Conditions.
aReagent and conditions: (a) (i) Ln*ꢀPd(OTf)2(MeCN)2, 2,6ꢀlutidine, NFSI, EtOH, 18 h.
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Table 1. Asymmetric Fluorination Reactions.
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Catalyst Loading
Entry
Substrate
Ln*
Temp (oC)
Yield (%th)a
ee/de (%)
(mol%)
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2
BINAP
BINAP
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20
ꢀ10
ꢀ10
ꢀ10
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DMꢀSEGPHOS
DTBMꢀSEGPHOS
XylylꢀBINAP
XylylꢀBINAP
BINAP
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97
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100
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99
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BINAP
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100
100
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9
XylylꢀBINAP
(S)ꢀBINAP
(R)ꢀBINAP
(S)ꢀBINAP
(R)ꢀBINAP
(S)ꢀBINAP
(S)ꢀBINAP
5
20
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(–)ꢀ13
(–)ꢀ13
(–)ꢀ13
(–)ꢀ13
(+)ꢀ13
(+)ꢀ13
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20
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ꢀ10
ꢀ10
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95
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83
91
90
94
0.5
n/d
n/d
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20
a Isolated yield after chromatography, uncorrected.
20 L Scale Synthesis (Scheme 3). The preparation of 14 from commercially available ethyl ester 2
required preparation of menthyl ester 13. Preparation or isolation of the corresponding acid proved
difficult, due to the tendency of this compound to undergo decarboxylation. Therefore, direct
transesterification methods were explored, leading to development of a DMAP catalysed process in
toluene with distillative removal of ethanol to drive the equilibrium.10 After a basic wash, the menthyl
ester was isolated by concentration to dryness.
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Scheme 3.a 20 L Scale Route to 1
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Reagent and conditions: (a) (i) (+)ꢀmenthol, 4ꢀDMAP, toluene, reflux, 7 d; (ii) (S)ꢀBINAPꢀ
Pd(OTf)2(MeCN)2, 2,6ꢀlutidine, NFSI, EtOH, 20 °C, 24 h, 70%, 100% de; (b) (i) BH3·DMS, THF,
reflux, 2 d; (ii) Boc2O, NaOH (aqueous), CH2Cl2, 20 °C, 15 h, 77%; (c) Tf2O, pyridine, ꢀ10 °C, 4 h,
92%; (d) NaN3, DMF, 20ꢀ30 °C, 6 h, 93%; (e) H2 (atmospheric), Pt/C (Johnson Matthey type 128),
THF, NH3 (aqueous), 20 °C, 39 h, quant.; (f) DIPEA, NMP, 110 °C, 17 h, 92%; (g) (i) Pd(diꢀtꢀbpf)Cl2
(Johnson Matthey Pdꢀ118), NaHCO3, 4:1 dioxane/water, reflux, 3 h; (ii) Silicycle Siꢀthiol, toluene,
60ꢀ65 °C, 2 h; (iii) HCl/dioxane, toluene, 60 °C; (h) (i) NaOH (aqueous); (ii) nꢀBuOAc/TBME, 57%
from 9.
In order for the fluorination chemistry to be carried out on multikilo scale, an improved, scalable
synthesis of the catalyst (S)ꢀBINAPꢀPd(OTf)2(MeCN)2 was required. Literature methods require either
the use of stoichiometric silver triflate,11 or handling of the palladium triflate intermediate,12 which is
very air sensitive. A telescoped process in acetonitrile followed by antisolvent crystallisation was
developed whereby multiple kilos of the bench stable catalyst could be readily prepared without
requirement for rigorous inertion or drying (see experimental section).
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Following fluorination chemistry as described above (Table 1, entry 15), optimisation of the reaction
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2
conditions allowed direct crystallisation of a mixture of product and the reduced NFSI byꢀproduct [Nꢀ
(phenylsulfonyl)benzenesulfonamide], avoiding the need for flash chromatography. This was achieved
using a subꢀstoichiometric amount (0.95 equivalents) of NFSI, avoiding the troublesome removal of
excess NFSI. Subsequent basic workꢀup removed the reduced NFSI byꢀproduct and crystallisation
removed other impurities as well as unreacted starting material. 2.5 kg of 14 was prepared using this
method, in 70% yield, 100% a/a HPLC purity and 100% de. The next steps were reduction and Boc
protection to give 4, an intermediate common to the medicinal chemistry route. The reduction
conditions described for ethyl ester 3 (Scheme 1) were successfully applied to the analogous menthyl
ester 14 on small scale. However, these conditions were unsuitable for scaleꢀup due to inherent safety
concerns.13 Diborane gas, which can be easily evolved from BH3·THF, has a low autoꢀignition
temperature of about 38-52 °C and a wide explosive range in air (0.8-90% vol).14 A number of
alternatives were evaluated for this conversion, including BH3·THF at 40 ºC, DEANB, LiAlH4 and Redꢀ
Al, all of which gave incomplete and/or messy reactions. Boc protection prior to reduction was also
explored, although competing reduction of the carbamate was problematic. BH3·DMS in THF at reflux
provided a safer alternative,13 giving clean reduction after 2 days provided >5 equivalents were used.
Methanol quench, followed by acidification with 2 M HCl allowed the menthol byꢀproduct to be
removed by extraction into toluene. Subsequent freeꢀbasing, Boc protection and crystallisation gave 4 in
77% yield on 1 kg scale.
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The triflation of 4 to 5 using triflic anhydride and triethylamine in dichloromethane was not in itself an
issue for early scaleꢀup. However, dichloromethane is incompatible with sodium azide15 used in the
subsequent step, so its avoidance was preferred. Use of other solvents with triethylamine as base gave
messy reactions, but switching to pyridine as both solvent and base provided a good alternative, with
improved product purity. The azide reaction to provide 6 could be carried out under ambient conditions,
and the requirement for chromatography was negated by the improved input quality. However, the
downstream hydrogenation was adversely affected. When the medicinal chemistry conditions of
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triethylamine/DCM were employed in the triflation, azide 6 derived from this sequence gave a failed
hydrogenation, although the reaction went cleanly after filtering off the catalyst and starting again.
Conversely, when pyridine was used in the triflation, the hydrogenation worked first time, but also
resulted in significant formation of a dimeric impurity 15.16 Addition of acetic acid did not significantly
suppress dimer formation and solvent screening provided limited success, with a best ratio of 4:1 using
ethyl acetate. Catalyst screening was therefore revisited, and, in combination with ammonia as an
additive,17 using platinum on carbon catalyst with THF solvent achieved quantitative hydrogenation to
amine 7 with only 0.3% dimer 15.
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The coupling of amine 7 with 5,7ꢀdichloroꢀ1,6ꢀnaphthyridine 8 was carried out in NMP with DIPEA
as base; conditions which gave a good reaction profile, with the exception of competing Boc
deprotection. The yield was improved by reducing the temperature from 130 ºC to 110 ºC, and addition
of water as antiꢀsolvent crystallised naphthyridine 9 in high purity directly from the reaction mixture.
The medicinal chemistry method for Suzuki–Miyaura coupling of 9 with pyrazole boronate 101 used a
high loading of tetrakis(triphenylphosphine)palladium(0) under microwave conditions and required
chromatography for purification. Focussed screening found that 0.5 mol% of bis(diꢀtertꢀ
butylphosphino)ferrocenepalladium dichloride in aqueous 1,4ꢀdioxane with sodium hydrogen carbonate
as base was a highly effective alternative. Palladium removal was effected by treatment with thiol
functionalised silica (Silacycle® Siꢀthiol) in toluene. It was found convenient to isolate the coupled
product by precipitation of 1 as the dihydrochloride, following Boc deprotection, hence avoiding
column chromatography. Free basing and operation of a fitꢀforꢀpurpose crystallisation from nꢀbutyl
acetate/TBME afforded 1 in reasonable overall yield (57% from 9) with excellent purity (99.8% a/a,
100% ee) and very low palladium content (2 ppm). A second crop of 1 (16%) was isolated by reworking
the liquors.
Multi-kilo Scale Synthesis (Scheme 4). The 20 L scale synthesis employed a number of concentrations
to dryness which would be impractical for pilot plant operation. To avoid a concentration to dryness, in
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the first stage of the synthesis, the menthyl ester solution in toluene was solvent swapped into ethanol
using an efficient ‘put and take’ distillation and this solution used directly in the fluorination chemistry
giving 14 in 68% yield, 100% de, over the two steps from 2.
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Operation of the boraneꢀdimethyl sulfide reduction of 14 on pilot plant scale was challenging due to
the high inventory required for complete reaction (6 equivalents). A very slow addition of the reaction
mixture into methanol to quench the excess reagent was required to limit the rate of hydrogen evolution.
The addition of hydrochloric acid and subsequent heat up to liberate the piperidine borane complex also
required very careful control. A large volume of basic bleach in the scrubbers prevented release of
dimethylsulfide to the atmosphere. DCM was replaced with TBME for the free basing of the
intermediate hydroxymethylpiperidine hydrochloride and Boc protection. Alcohol 4 was produced in a
single batch in 72% yield (23.3 kg), comparable to the first scaleꢀup campaign.
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On further scaleꢀup to pilot plant, the triflation, azide formation, hydrogenation and coupling with
naphthiridine were telescoped together such that no intermediates were isolated between compounds 4
and 9. The triflation was run as before, in pyridine, with extraction into TBME using citric acid to wash
out the pyridine. The concentrated TBME solution was diluted with DMF and reacted with sodium
azide. This was slower than the reaction in neat DMF but allowed avoidance of evaporation to dryness
on large scale. To ensure safe operation, vessel choice and fill volume were optimized for good stirring
to keep the azide suspended. The vessel was also pretreated with dilute hydrochloric acid, prior to
neutralisation and cleaning to remove acid residues, to ensure that no metal particulates were present. A
solvent screen for the hydrogenation, revealed that TBME/ammonia could be used in place of THF,
facilitating telescoping of this step.
The coupling of amine 7 with the napthyridine 8 was accomplished in DMF with 1 volume of TBME
present, thus allowing a concentrated solution of 7 in TBME to be used directly. Careful water addition
allowed 9 to be crystallised from the reaction mixture in 38% overall yield from 4, with excellent purity
(HPLC 99.2% a/a).
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Only minor modifications of the Suzuki–Miyaura/Boc deprotection protocol were envisaged to facilitate
pilot plant preparation of 1. However, use of functionalised silica for palladium removal was
unattractive. In addition, the combination of refluxing dioxane and liberation of carbon dioxide as a
consequence of using sodium hydrogen carbonate as base was regarded as undesirable because of the
risk of loss of a class A VOC to the atmosphere. However, investigation of reactions at subꢀreflux
temperature and with alternative bases uncovered an underlying issue with the Suzuki–Miyaura
chemistry. It was found that rigorous exclusion of oxygen was required to avoid stalling, despite the fact
that the initial campaign had been successfully performed without special degassing precautions.
Aqueous dioxane at reflux proved to be preferred over alternative solvent combinations, particularly to
minimise protodeboronation of 10. Sodium hydrogen carbonate was replaced by sodium carbonate as
base. Environmental loss of dioxane was kept well below acceptable limits. A larger excess of boronate
10 (1.4 instead of 1.2 equivalents) was used compared to the first campaign to ensure robust
consumption of chloride 9. Palladium removal was performed by treating the aqueous dioxane reaction
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mixture with Lꢀcysteine at 60 °C and a CUNO charcoal filtration after extractive workup and dilution
with toluene. Boc deprotection was carried out with HCl/dioxane in toluene at 60 °C as before. The
dihydrochloride salt of 1 (HPLC 96.4% a/a) was isolated with comparable purity to the first delivery
campaign. However, an unidentified minor impurity caused problems with the subsequent free base
crystallisation. A rework of 1 dihydrochloride was instigated to obviate this issue. Hence, 1
dihydrochloride was slurried in industrial methylated spirit (IMS) at 25 °C then filtered. 1
Dihydrochloride of high purity (HPLC 100% a/a) and low palladium content (6 ppm) was isolated in
84% overall yield from 9 for the telescoped Suzuki–Miyaura/Boc deprotection and IMS slurry.
The hydrochloride salt of 1 was freeꢀbased with aqueous sodium carbonate and extracted into ethyl
acetate. The organic layer was azeotropically dried under reduced pressure and 1 was crystallized from
ethyl acetate/diisopropyl ether. The slurry was size reduced, by rotorꢀstator wetꢀmilling, before 1 was
isolated as a yellow solid in 73% yield from the hydrochloride salt as a quarter hydrate, labelled as Form
1, of excellent purity (100% a/a, 100% ee, Pd 2 ppm). A further 8% yield of 1 was subsequently isolated
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as a second crop. A polymorph screen found two polymorphs of similar stability (Form 1 and Form 2)
and identified a number of solvates. From the data generated, Form 2 seems to be more stable than Form
1 at ambient temperatures (lower solubility in several systems, turnover in competitive experiments).
However, throughout the development of the particle forming step, Form 2 has been challenging to
prepare which may be due to the very close energy relationship between the two forms. Ostwalds rule18
of stages suggests that the least stable polymorph of a given system will crystallize first and then
turnover to the more stable polymorph over time. In this case, if the driving force to go from Form 1 to
Form 2 is very small in terms of an absolute energy difference, then the kinetics will be very slow. This
has been demonstrated in a turnover experiment which took more than a week to give significant
amounts of Form 2. Both Forms 1 and Form 2 were found to have very similar dissolution properties in
physiological media, so producing either Form 1 or Form 2 was deemed acceptable for initial safety and
clinical studies.
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Scheme 4.a Multiꢀkilo Scale Route to 1.
a
Reagents and conditions: (a) (i) (+)ꢀmenthol, 4ꢀDMAP, toluene; (ii) (S)ꢀBINAPꢀPd(OTf)2(MeCN)2,
2,6ꢀlutidine, NFSI, EtOH, 68%, 100% de; (b) (i) BH3·DMS, THF; (ii) Boc2O, NaOH (aqueous), TBME,
72%; (c) Tf2O, pyridine; (d) NaN3, TBME/DMF; (e) H2 (2 barg), Pt/C, TBME, NH3 (aqueous); (f)
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DIPEA, TBME/NMP, 38% (from 4); (g) (i) Pd(diꢀtꢀbpf)Cl2, Na2CO3, dioxane/water; (ii) HCl/dioxane,
toluene; (iii) IMS, 84%; (h) (i) Na2CO3 (aqueous), EtOAc; (ii) EtOAc, diisopropyl ether, 73% (+ 8%
second crop).
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9
In conclusion, a combined chiral auxiliary and chiral catalyst mediated diastereoselective fluorination
was developed and successfully operated on large scale. 8 kg of SYK inhibitor 1 was synthesised using
this methodology via a singleꢀbatch strategy. This involved development of safe pilot plant scale
processes for reduction to prepare alcohol 4, subsequent azide introduction, and a robust lateꢀstage
SuzukiꢀMiyaura coupling.
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EXPERIMENTAL SECTION
General procedures. All reagents and solvents used were obtained commercially unless stated, and
were employed without further purification. The experimental conditions below refer to the procedures
used for the multikilogram pilotꢀplant campaign. NMR data were obtained on Bruker AV 400, AV 500
or AV 700 spectrometers. High resolution mass spectrometry data were obtained a ThermoꢀFinnigan
Orbitrap Fourierꢀtransform mass spectrometer running in positive electrospray ionisation mode.
[(S)ꢀBINAP]bis(acetonitrile)palladium(II) ditriflate
Palladium acetate (300 g) was dissolved in acetonitrile (1.2 L) and stirred at 20±3 °C for 1 h. The
reaction mixture was cooled to 0±3 °C. Trifluoromethanesulfonic acid (225 mL) was added over
30 min, maintaining the temperature below 3 °C, then rinsed in with acetonitrile (90 mL). After stirring
for 18 min at 0±3 °C the reaction mixture was heated to 20±3 °C and stirred for 31 min. (S)ꢀBINAP
(831 g) was added followed by a wash of acetonitrile (90 mL) and the mixture was stirred at 20±3 °C
for 2 h. Diisopropyl ether (3 L) was added over 30 min to give a slurry which was aged for 30 min. The
solid was filtered off under suction and washed with acetonitrile:diisopropyl ether (1:3, 2.4 L) followed
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Organic Process Research & Development
by diisopropyl ether (2.4 L). The product was dried under vacuum at 20±3 °C to afford a yellow solid
1304g (88%).
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(3S)ꢀ(1S,2R,5S)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl 3ꢀfluoroꢀ2ꢀoxopiperidineꢀ3ꢀcarboxylate 14.
9
Ethyl 2ꢀoxopiperidineꢀ3ꢀcarboxylate 2 (37.0 kg), 4ꢀdimethylaminopyridine (DMAP) (12.95 kg),
(1S,2R,5S)ꢀmenthol (35.2 kg) were charged. Toluene (370 L) was added and the reaction mixture heated
to reflux, and stirred under constant volume distillation by adding toluene at the same rate as toluene is
removed for 5 days. The reaction mixture was cooled to 22±3 °C and washed with 2 N aqueous
hydrochloric acid (2 x 148 L) and then water (148 L). The reaction mixture was distilled under
atmospheric pressure to ca. 111 L, ethanol (666 L) was added, the mixture distilled under atmospheric
pressure to ca. 111 L then cooled to 22±3 °C. NꢀFluorobenzenesulfonimide (68.1 kg) was added,
followed by Pd(S)ꢀBINAP(OTf)2 (2.26 kg), washing in the residual Nꢀfluorobenzenesulfonimide and
catalyst with further ethanol (55 L). The reaction mixture was cooled to <5 °C and 2,6ꢀlutidine (13.0 L)
was charged dropwise keeping the temperature <10 °C. The reaction mixture was stirred at 22±3 ºC for
42 h. The reaction mixture was then cooled to 0 ºC and stirred for an additional 2 h. The precipitated
solids were isolated by filtration, washed with chilled ethanol (111 L) and dried under vacuum overnight
at 40 ºC. The solids were reꢀcharged to a vessel at 22±3 ºC, followed by dichloromethane (303 L) and
stirred until a solution was obtained. The solution was washed sequentially with 2 M aqueous sodium
hydroxide (185 L), water (185 L), 2 N aqueous hydrochloric acid (185 L) and finally water (185 L).
IMS (277 L) was added and the mixture was distilled under atmospheric pressure to ca. 111 L, then
diluted with IMS (74 L). Water (185 L) was added over 2 h whilst maintaining the temperature at
22±3 ºC then the mixture was cooled to 0±3 °C and stirred for a further 2 h. The solid was collected by
filtration, washed with chilled water/IMS (3:1, 74 L) and dried under vacuum at 40 °C to give 14
(43.7 kg, 68%) as an orange crystalline solid (mp 167ꢀ169°C).
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1H NMR (500 MHz, CDCl3) δ 0.77 (3H, d, J = 5 Hz), 0.89 (3H, d, J = 10 Hz), 0.92 (3H, d, J = 5 Hz),
1.03ꢀ1.11 (2H, m), 1.43ꢀ1.55 (2H, m), 1.67ꢀ1.74 (2H, m), 1.85ꢀ2.06 (4H, m), 2.22ꢀ2.37 (2H, m), 3.37ꢀ
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3.46 (2H, m), 4.84 (1H, dt, J = 10, 5 Hz), 7.35 (1H, brs). MS Found for C16H27FNO3 [M+H] =
1
2
3
300.1965, Calc for C16H27FNO3 [M+H] = 300.1970.
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1,1ꢀDimethylethyl (3S)ꢀ3ꢀfluoroꢀ3ꢀ(hydroxymethyl)ꢀ1ꢀpiperidinecarboxylate 4.
9
(3S)ꢀ(1S,2R,5S)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl 3ꢀfluoroꢀ2ꢀoxopiperidineꢀ3ꢀcarboxylate 14 (41.85 kg)
was suspended in THF (240 L) and treated with borane dimethyl sulfide complex (64.0 kg). The
resulting solution was stirred at 67±3 °C for 43 h. The reaction mixture was cooled to 0±5 °C and
slowly added to cold (0±5 °C) methanol (126 L) over at least 90 min, maintaining the internal
temperature below 20 °C. 2 M Hydrochloric acid (166 L) was added over at least 60 min, maintaining
the internal temperature below 20 °C. The mixture was stirred at 20±3 °C for at least 30 min then stirred
at 60±5 °C for at least 60 min then cooled to 20ꢀ25 °C. Toluene (168 L) was added, the mixture stirred
for 15 min then filtered. The filter cake was washed with toluene (84 L). The filtrate was separated and
the lower acidic aqueous phase was run off. The filter cake was washed with 2 M hydrochloric acid
(83 L) and the wash used for a second extraction of the toluene phase. The acidic aqueous phases were
combined. 32% Sodium hydroxide solution (105 kg) was added over at least 60 min, maintaining the
temperature below 25 °C. The mixture was diluted with TBME (84 L). A 70% w/w solution of diꢀtertꢀ
butylꢀdicarbonate in TBME (48.3 kg) was added and rinsed in with more TBME (63 L). The twoꢀphase
mixture was stirred vigorously at 20±5 °C for 2 h. The phases were separated and the upper organic
phase washed with 5% w/w sodium chloride in water (168 L). The aqueous phase was extracted with a
further portion of TBME (168 L) and the extract was washed with the previously used brine. The
combined organics were diluted with heptane (168 L) and concentrated by vacuum distillation to ca.
168 L at 40±3 °C. Heptane (168 L) was added and the mixture concentrated by vacuum distillation to
ca. 252 L at 40ꢀ45 °C. The solution was seeded at 40ꢀ45 °C with 4 (84 g). The mixture was concentrated
by vacuum distillation at 40ꢀ45 °C to ca. 168 L then the concentrate was cooled and stirred at 20±5 °C
for 90 min. The solid was filtered off, washed with heptane (2 x 42 L) and dried under vacuum at
25±5 °C to give 4 (23.3 kg, 72%) as a colourless solid (mp 97ꢀ98°C).
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1H NMR (500 MHz, DMSOꢀd6) δ 1.39 (9H, s), 1.44ꢀ1.76 (4H, m), 2.82ꢀ3.08 (2H, m), 3.35ꢀ3.48 (2H,
m), 3.80 (1H, d, J = 10 Hz), 3.93 (1H, brs), 4.99 (1H, t, J = 5 Hz). MS Found for C11H21FNO3 [M+H] =
234.1499, Calc for C11H21FNO3 [M+H] = 234.1500.
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1,1ꢀDimethylethylꢀ(3R)ꢀ3ꢀ{[(7ꢀchloroꢀ1,6ꢀnaphthyridinꢀ5ꢀyl)amino]methyl}ꢀ3ꢀfluoroꢀ1ꢀ
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piperidinecarboxylate 9.
1,1ꢀDimethylethyl (3S)ꢀ3ꢀfluoroꢀ3ꢀ(hydroxymethyl)ꢀ1ꢀpiperidinecarboxylate 4 (21.0 kg) dissolved in
pyridine (64 L) was cooled to ꢀ10 °C. Triflic anhydride (16.8 L) was added over 1 h, keeping the
contents below 5 °C. The reaction was stirred at ꢀ10±3 °C for 90 min. The reaction was warmed to 0 °C.
TBME (105 L) was added, followed by 50 wt% citric acid (105 L) over 30 min. The mixture was stirred
at 20 °C for at least 5 min, allowed to settle and the layers separated. The organic phase was further
washed with 50 wt% citric acid solution (105 L), water (63 L), 7 wt% sodium bicarbonate solution (63
L) and water (63 L) The resulting organic solution was partially dried by distilling down to ca. 61 L,
adding a further aliquot of TBME (53 L) and distilling to ca. 53 L. This solution was assayed and added
to a stirred mixture of sodium azide (5.2 kg) in DMF (47 L) and TBME (26 L) at room temperature. The
resulting suspension was stirred at 22±3 °C for 47 h. Water (73.5 L) was added to the reaction mixture
and the mixture was stirred for at least 5 min before allowing to settle and separating. The aqueous
phase was back extracted with TBME (63 L). The TBME phases were combined and washed with water
(2 x 42 L). The TBME solution was diluted with further TBME to give a total volume of ca. 273 L and
charged to a pressure reactor. 10% Pt/C (type 128, 50% wet paste, 168 g) and 33% aqueous ammonia
(42 L) were added. The reaction mixture was hydrogenated at 2 barg and 22±3 °C for 22 h. The reaction
mixture was filtered through a bed of celite and washed with TBME (63 L). The lower aqueous phase
was removed and the organic washed with 2 N aqueous hydrochloric acid (2 x 42 L). The aqueous layer
was basified with 32 wt% aqueous sodium hydroxide and extracted with TBME (2 x 105 L). The TBME
phases were combined, washed with water (42 L) and evaporated under atmospheric distillation to give
a concentrated TBME solution (ca. 21 L). NMP (126 L) was added, followed by 5,7ꢀdichloroꢀ1,6ꢀ
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naphthyridine (6.34 kg) and diisopropylethylamine (36.8 L). The mixture was stirred at 105±5 °C for 8
h. The solution was cooled to 60ꢀ65 °C and water (84 L) was added over at least 15 min. The mixture
was further cooled to 40ꢀ45 °C and seeded with authentic 1,1ꢀdimethylethylꢀ(3R)ꢀ3ꢀ{[(7ꢀchloroꢀ1,6ꢀ
naphthyridinꢀ5ꢀyl)amino]methyl}ꢀ3ꢀfluoroꢀ1ꢀpiperidinecarboxylate 9 (6.3 g). The mixture was aged for
at least 1 h to give a slurry. Water (13 L) was added over at least 15 min, the mixture was aged for at
least 30 min and then cooled to 20ꢀ25 °C over at least 30 min. The mixture was aged for at least 2 h.
The solid was collected under suction. The filter cake was washed with 1:2 v/v NMP/water (13 L) then
water (2 x 26 L) and dried under vacuum at 40±5 °C to give 9 (13.5 kg, 38%, 99.2% a/a HPLC purity)
as a colourless solid (mp 158ꢀ159°C).
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1H NMR (500 MHz, DMSOꢀd6) δ 1.33 (9H, brd, J = 20 Hz), 1.57ꢀ1.88 (4H, m), 2.86ꢀ3.11 (2H, m),
3.73ꢀ3.92 (4H, m), 7.03 (1H, s), 7.52 (1H, dd, J = 10, 5 Hz), 8.23 (1H, t, J = 5 Hz), 8.79 (1H, d, J =
10 Hz), 8.93 (1H, d, J = 5 Hz). MS Found for C19H25ClFN4O2 [M+H] = 395.1645, Calc for
C19H25ClFN4O2 [M+H] = 395.1645.
7ꢀ[1ꢀ(1,1ꢀDimethylethyl)ꢀ1Hꢀpyrazolꢀ4ꢀyl]ꢀNꢀ{[(3S)ꢀ3ꢀfluoroꢀ3ꢀpiperidinyl]methyl}ꢀ1,6ꢀnaphthyridinꢀ
5ꢀamine dihydrochloride 1.2HCl
A degassed mixture of 1,1ꢀdimethylethylꢀ(3R)ꢀ3ꢀ{[(7ꢀchloroꢀ1,6ꢀnaphthyridinꢀ5ꢀyl)amino]methyl}ꢀ3ꢀ
fluoroꢀ1ꢀpiperidinecarboxylate
9
(13.45 kg), 1ꢀ(1,1ꢀdimethylethyl)ꢀ4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀ
dioxaborolanꢀ2ꢀyl)ꢀ1Hꢀpyrazole 10 (11.9 kg) sodium carbonate (10.8 kg) and 1,1ꢀbis(diꢀtertꢀ
butylphosphino)ferrocene palladium dichloride (111 g) in 1,4ꢀdioxane (108 L) and water (54 L) was
stirred at reflux (88±2 °C) for 4 h. The reaction mixture was diluted with water (54 L) and Lꢀcysteine
(1.4 kg) was added. The mixture was stirred at 60±3 °C for 34 h. Toluene (54 L) was charged and the
phases separated at 50±3 °C. The hot organic phase was passed through a CUNO cartridge containing
charcoal (type R55S), washing through with hot (50 °C) toluene (54 L). The organic solution was
concentrated to ca. 160 L by vacuum distillation. The solution was diluted with 1,4ꢀdioxane (54 L) and
toluene (54 L), heated to 60±3 °C and treated with 4 M hydrogen chloride in 1,4ꢀdioxane (40 L). The
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mixture was stirred at 60±3 °C for 25 h. The thick slurry was cooled to 20±3 °C and aged for 8 h. The
solid was filtered and washed with 1:2 v/v 1,4ꢀdioxane/toluene (40 L), toluene (40 L) then TBME (2 x
40 L). The product was dried in vacuo at 40±5 °C to give crude 7ꢀ[1ꢀ(1,1ꢀdimethylethyl)ꢀ1Hꢀpyrazolꢀ4ꢀ
yl]ꢀNꢀ{[(3S)ꢀ3ꢀfluoroꢀ3ꢀpiperidinyl]methyl}ꢀ1,6ꢀnaphthyridinꢀ5ꢀamine dihydrochloride 1.2HCl. The
crude product was slurried in IMS (230 L) and stirred at 25±3 °C for 8 h. The mixture was warmed to
50±3 °C and stirred for 1 h, cooled to 20±3 °C over 1 h and stirred at this temperature for 1 h. The solid
was collected by filtration and washed with IMS (30 L) then TBME (2 x 45 L). The solid was dried
under vacuum at 40 °C to give 7ꢀ[1ꢀ(1,1ꢀdimethylethyl)ꢀ1Hꢀpyrazolꢀ4ꢀyl]ꢀNꢀ{[(3S)ꢀ3ꢀfluoroꢀ3ꢀ
piperidinyl]methyl}ꢀ1,6ꢀnaphthyridinꢀ5ꢀamine dihydrochloride 1.2HCl (13.1 kg, 84%, 100% a/a HPLC
purity) as an orange solid (mp 243ꢀ244°C).
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1H NMR (500 MHz, DMSOꢀd6) δ 1.61 (9H, s), 1.80ꢀ1.99 (4H, m), 2.85ꢀ2.92 (1H, m), 3.14ꢀ3.46 (4H,
m), 3.97ꢀ4.09 (2H, m), 7.38 (1H, s), 7.71 (1H, dd, J = 10, 5 Hz), 8.20 (1H, s), 8.51 (1H, s), 8.63ꢀ8.70
(2H, m), 9.03 (1H, d, J = 5 Hz), 9.31 (1H, d, J = 10 Hz), 9.64ꢀ9.71 (1H, m).
7ꢀ[1ꢀ(1,1ꢀDimethylethyl)ꢀ1Hꢀpyrazolꢀ4ꢀyl]ꢀNꢀ{[(3S)ꢀ3ꢀfluoroꢀ3ꢀpiperidinyl]methyl}ꢀ1,6ꢀnaphthyridinꢀ
5ꢀamine 1
7ꢀ[1ꢀ(1,1ꢀDimethylethyl)ꢀ1Hꢀpyrazolꢀ4ꢀyl]ꢀNꢀ{[(3S)ꢀ3ꢀfluoroꢀ3ꢀpiperidinyl]methyl}ꢀ1,6ꢀnaphthyridinꢀ
5ꢀamine dihydrochloride 1.2HCl (13.1 kg) was dissolved in water (92 L) and the solution basified to pH
10ꢀ11 with a solution of sodium carbonate (7.34 kg) in water (39 L). The resulting mixture was
extracted with ethyl acetate (1 x 130 L and 1 x 26 L). The extracts were combined and washed with
water (2 x 26 L), filtered through a line filter, washing through with ethyl acetate (65 L), and distilled
under reduced pressure to ca. 52 L, keeping the contents temperature ≤40 °C. Ethyl acetate (65 L) was
added and the solution distilled under reduced pressure to ca. 52 L, keeping the contents temperature
≤40 °C. Ethyl acetate (65 L) was added and the solution distilled under reduced pressure to ca. 39 L,
keeping the contents temperature ≤40 °C. The mixture was cooled to 20 °C and a further charge of ethyl
acetate (20 L) was added (to bring the ethyl acetate volume to 5 vol with respect to 1). The solution was
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heated to 60±3 °C and diisopropyl ether (53 L) was added slowly keeping the temperature above 50 °C.
The mixture was seeded at 50 °C with authentic 7ꢀ[1ꢀ(1,1ꢀdimethylethyl)ꢀ1Hꢀpyrazolꢀ4ꢀyl]ꢀNꢀ{[(3S)ꢀ3ꢀ
fluoroꢀ3ꢀpiperidinyl]methyl}ꢀ1,6ꢀnaphthyridinꢀ5ꢀamine 1 (10.56 g) and diisopropyl ether (53 L) was
added keeping the temperature above 45 °C. The mixture was cooled to 45 °C, stirred at this
temperature for 1 h then cooled to 3 °C over 3 h. The slurry was stirred at 3 °C for 1 h then wetꢀmilled.
The slurry was reꢀcooled to 3 °C and stirred for 4 h. The solid was collected by filtration, washed with
diisopropyl ether (53 L) and dried at 40 °C under vacuum to give 7ꢀ[1ꢀ(1,1ꢀdimethylethyl)ꢀ1Hꢀpyrazolꢀ
4ꢀyl]ꢀNꢀ{[(3S)ꢀ3ꢀfluoroꢀ3ꢀpiperidinyl]methyl}ꢀ1,6ꢀnaphthyridinꢀ5ꢀamine 1 (8.01 kg, 73%, 100% a/a
HPLC purity) as a yellow solid, form 1 by XRPD (mp 150ꢀ151°C).
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1H NMR (700 MHz, CDCl3) δ 1.63 (1H, m), 1.66 (9H, s), 1.74ꢀ1.82 (2H, m), 2.01 (1H, m), 2.72 (1H,
m), 2.85ꢀ2.94 (2H, m), 3.03 (1H, m), 3.87 (1H, m), 4.15 (1H, m), 5.76 (1H, t, J = 5.8 Hz), 7.25 (1H, dd,
J = 8.2, 4.3 Hz), 7.36 (1H, s), 8.04 (1H, s), 8.08 (2H, m), 8.88 (1H, d, J = 4.3 Hz). 13C NMR
(100.6 MHz, CDCl3) δ 23.6 (d, JC,F = 2.7 Hz), 29.8, 32.1 (d, JC,F = 21.5 Hz), 45.8, 46.8 (d, JC,F
=
21.1 Hz), 51.9 (d, JC,F = 23.8 Hz), 58.7, 94.1 (d, JC,F = 172 Hz), 106.4, 111.8, 119.5, 123.1, 124.5,
130.1, 137.4, 148.1, 153.5, 153.8, 155.2. MS Found for C21H28FN6 [M+H] = 383.2355, Calc for
C21H28FN6 [M+H] = 383.2354.
ACKNOWLEDGMENT
This paper is dedicated in memory of Lois Vernon, a skilled chemist and highly valued member of
Product Development. We thank our medicinal chemistry colleagues for work on the original synthetic
route and useful discussions, and our partners in analytical sciences, process safety, pilot plant
operations, technical sourcing and particles sciences.
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