Development of a Novel Process for the Kilogram-Scale Synthesis of Spiro[1 H-pyrido[2,3- d][1,3]oxazine-4,4′-piperidine]-2-one

Article abstract of DOI:10.1021/acs.oprd.8b00202

Spiro[1H-pyrido[2,3-d][1,3]oxazine-4,4′-piperidine]-2-one (3) is a key building block in many biologically active compounds. The synthesis of this compound, as reported in the literature, is low-yielding. We have discovered and developed a robust, high-yielding process to generate 3 as a bis-HCl salt using alternative starting materials and reaction conditions. The developed process was successfully demonstrated on a kilogram scale. A two-batch kilo lab campaign generated the bis-HCl salt of 3 in >99 HPLC area percent purity and 77% overall yield.

Full text of DOI:10.1021/acs.oprd.8b00202

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Full Paper
Development of a Novel Process for the Kilogram Scale Synthesis
of Spiro[1H-pyrido[2,3-d][1,3]oxazine-4,4'-piperidine]-2-one
Dale R Mowrey, James J. Reif, Karen L. Milkiewicz, and Shawn P. Allwein
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00202 • Publication Date (Web): 26 Jul 2018
Downloaded from http://pubs.acs.org on July 26, 2018
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Development of a Novel Process for the Kilogram
Scale Synthesis of Spiro[1Hꢀpyrido[2,3ꢀ
d][1,3]oxazineꢀ4,4'ꢀpiperidine]ꢀ2ꢀone
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Dale R. Mowrey, James J. Reif, Karen L. Milkiewicz, and Shawn P. Allwein*
Teva Pharmaceuticals, 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
*Email: shawn.allwein@tevapharm.com
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TOC figure
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2 HCl
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3 - 2HCl
77% Yield
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ABSTRACT Spiro[1Hꢀpyrido[2,3ꢀd][1,3]oxazineꢀ4,4'ꢀpiperidine]ꢀ2ꢀone (3) is a key building
block in many biologically active compounds. The synthesis of this compound, as reported in the
literature, is low yielding. We have discovered and developed a robust, highꢀyielding process to
generate 3 as a bisꢀHCl salt using alternative starting materials and reaction conditions. The
developed process was successfully demonstrated on kilogram scale. A twoꢀbatch kilo lab
campaign generated the bisꢀHCl salt of 3 in > 99 HPLC area percent purity and 77% overall
yield.
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INTRODUCTION Spiro[1Hꢀpyrido[2,3ꢀd][1,3]oxazineꢀ4,4'ꢀpiperidine]ꢀ2ꢀone (3) is an
important fragment in various CGRP receptor antagonists,1 TRPA1 modulators,2 muscarinic
acetylcholine receptor agonists,3 β3ꢀadrenergic receptor agonists,4 CꢀC chemokine receptorꢀ8
antagonists,5 and MCPꢀ1 antagonists.6
Several patents describe the synthesis of 3.1nꢀp, rꢀu, 3b In all cases, the synthetic route is identical
to that shown in Scheme 1. 2ꢀAminoꢀ6ꢀchloropyridine is protected as its Boc derivative through
the use of sodium hexamethyl disilazide (NaHMDS) and diꢀtertꢀbutyl dicarbonate (Boc2O).
After directed orthoꢀmetalation with butyl lithium under cryogenic conditions, benzyl 4ꢀ
oxopiperidineꢀ1ꢀcarboxylate is added to the resulting anion. Intramolecular cyclization of the
intermediate followed by hydrogenation to deprotect the CBZ group and remove the chlorine
affords 3 in a 17% overall yield over 3 steps.
Scheme 1: Literature Synthesis of 3
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1) BuLi, Hex.,
TMEDA, THF
-20 to -78 °C
NaHMDS
Boc2O
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THF, 0 °C
Step 1
2)
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68% Yield
Step 2a
H2
Et3N, Pd/C
40 °C
DCM
EtOH
Step 2b
Step 3
2
3
4
15-30% Yield
85% Yield
ROUTE DEVELOPMENT For a recent project, kilogram quantities of 3 were required. The
published route has several issues that were necessary to address before scaling this process.
According to the literature,1k ortho metalation and cyclization attempts without the chlorine
group present were unsuccessful. The use of the chloro group, however, necessitated its removal
via hydrogenation, which can be hazardous on large scale. Additionally, the chloro was not
completely removed during the hydrogenation step, and chromatography was required to
separate the chlorinated product 4 from 3. Step 2a and 2b were also problematic from a scaleꢀup
perspective. This overall transformation was very low yielding, had poor reproducibility, and
required cryogenic conditions.
In order to circumvent these issues, an alternative route was developed. Utilization of 3ꢀ
bromoꢀ2ꢀaminopyridine as the starting point for the synthesis provided two advantages. This
readily available commercial starting material, which is comparable in price to 2ꢀaminoꢀ6ꢀ
chloropyridine, allowed directed anion formation while avoiding the need to later remove the
chlorine. In addition, use of 1ꢀBocꢀ4ꢀpiperidone in place of 1ꢀCbzꢀ4ꢀpiperidone allowed the
final hydrogenation conditions to be avoided completely.
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Preparation of the Boc protected 3ꢀbromoꢀ2ꢀaminopyridine was straight forward, but
installation of the spirocycle remained challenging. Though a CO2 quench of the lithium anion
showed that no 3ꢀbromoꢀ2ꢀaminopyridine remained, LCMS showed that the major product after
addition of 1ꢀBocꢀ4ꢀpiperidone was 2ꢀaminopyridine. It was hypothesized based on this data
that the lithium species was not stable even at ꢀ40 °C.
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Generation of the anion with isoꢀpropyl magnesium chloride (iPrMgCl) provided a stable
magnesium species at 0ꢀ15 °C and led to an effective addition of this species to 1ꢀBocꢀ4ꢀ
piperidone. However, the final ring closure to form the spirocycle was not viable using these
conditions. It was hypothesized that the magnesium in the intermediate was impeding the ring
closure, and in fact, when the intermediate was quenched to remove the magnesium and
subjected to potassium tꢀbutoxide (KOtBu), the ring closure progressed smoothly. The product
was isolated as a potassium salt by direct filtration of the reaction mixture. After acidic Boc
deprotection using HCl, 3 - 2HCl was isolated via direct filtration in ~ 77% yield over three
steps from 3ꢀbromoꢀ2ꢀaminopyridine. This yield is nearly 4 times the yield of the original
literature route. The optimized synthesis is shown in Scheme 2.
Scheme 2. Modified Synthesis of 3 - 2HCl
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1) iPrMgCl
2MeTHF
NaHMDS
Boc2O
2)
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THF
Heptane
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84% Yield
Step 1
3) NH4 Cl (aq)
Step 2a
6
2 HCl
KOtBu/THF
Step 2b
HCl, IPA
Step 3
7
3 - 2HCl
92% Yield
Quant. Yield
PROCESS DEVELOPMENT With proof of concept that the new spirocycle formation
conditions were superior, the focus was shifted to optimizing the process for scale. The Boc
protection of 3ꢀbromoꢀ2ꢀamino pyridine suffered from several process issues. It had emulsion
issues in the workup, suffered from stability issues in the final solvent switch procedure, and was
generally volume inefficient.
The initial aqueous quench of the reaction resulted in a cloudy emulsion, making separation of
the layers difficult. This was found to be directly related to the pH of the mixture after the HCl
quench. The emulsion was successfully eliminated by adjusting the mixture, after the water
quench, to pH 7ꢀ7.4 using 6N HCl and then adding a dilute 20 wt% solution of ammonium
chloride (final pH 6.5ꢀ6.9). This use of ammonium chloride not only broke up the residual rag
layer, but also helped to ensure that a slight overcharge at the end of the pH adjustment didn’t
drive the pH low enough to cause deprotection of the Boc group.
The lab scale isolation was done by drying the organic layer over sodium sulfate followed by
concentration to a residue. Trituration of the residue in EtOH at 70 °C gave filterable solids. To
scale up this procedure it was adjusted to a solvent switch in which the water was azeotroped off
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and then anhydrous ethanol was used portion wise in a azeotropic distillation to reduce the
amount of residual 2ꢀMeTHF to minimize losses. Unfortunately, the elevated temperatures
required to make the distillation times viable on scale (80 °C, 100 mbar) caused the formation of
significant impurities. An ethyl carbamate impurity began forming at 45ꢀ50 °C. The long heat
times during the concentration led to the production of up to 15% of the ethyl carbamate
impurity over 1 hour in ethanol. Also, at elevated temperatures the Boc group was unstable.
These impurities tracked throughout the subsequent steps and were not rejected in the final
isolation of 3 - 2HCl.
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To eliminate these impurities the solvent system was optimized to reduce the temperature in
the solvent switch. The reaction solvent was changed from 2ꢀMeTHF to the lower boiling THF.
In addition, alternative antiꢀsolvents which couldn’t react with the product were evaluated.
EtOAc and heptane looked promising, but EtOAc generated tacky final solids which retained
HMDS that tracked through to 3 - 2HCl. Heptane proved to be ideal, and the use of THF and
heptane prevented the formation of the ethyl carbamate impurity and allowed the distillation to
proceed at 40 °C, thereby eliminating the deprotection issues. Solids were isolated from this
precipitation in > 99 LCAP (HPLC Area%) with 10% losses.
Finally, early lab experiments were run at a volume of 25ꢀ30 times of the starting material, too
inefficient for an effective scaleꢀup campaign. 1N NaHMDS was the source of a significant
portion of this volume. Making a more concentrated NaHMDS solution in house allowed for use
of a 2N NaHMDS solution. Just after the scaleꢀup detailed in this paper, a commercial supplier
of bulk 2N NaHMDS was identified and this reagent was shown to be equivalent to the material
made in house. Use of this material in future scaleꢀup would eliminate the need to manipulate
solid NaHMDS.
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The volumes were further reduced by adding solid 3ꢀbromoꢀ2ꢀaminopyridine directly to the
2M NaHMDS/THF solution and then adding Boc2O in 0.5 volumes of THF rather than the
original 15 volumes. Evaluation of the exotherms for these two additions informed the decision
to handle them differently. The addition of 3ꢀbromoꢀ2ꢀaminopyridine generated 32.5 kJ/mol
which, given the reaction mass, was equivalent to a modest ~ 8 °C adiabatic temperature rise. It
was therefore deemed acceptable to add the 3ꢀbromoꢀ2ꢀaminopyridine in one portion. However,
addition of Boc2O generated 289 kJ/mol or ~ 61 °C adiabatic temperature rise. This was a
significant thermal event and prompted the use of a solution of Boc2O in THF to allow the
addition rate to assist in controlling the batch temperature. Overall, the changes to the NaHMDS
concentration, and to the additions of the other two reagents led to a more acceptable 10ꢀ12 total
volumes. This procedure was successfully scaled up in two batches in the kilo lab to generate
2.3 kg of 5 in > 99 LCAP.
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The spirocycle formation also required some optimization for scaleꢀup. It was observed that
when the equivalents of iPrMgCl was minimized, the reaction was particularly sensitive to water
in the solvents. In addition, the aqueous quench of the intermediate contained solids, and the
final product slurry was very thick.
During the development of this step, the charge of iPrMgCl was optimized to 2.2 equivalents.
With this charge set, it was found that THF with 200ꢀ500 ppm of water caused quenching of the
organometallic. This promoted the formation of high levels of desꢀbromo impurity which
tracked through to 3 - 2HCl. For the kilo lab scale which is detailed in this paper, the purchase
of anhydrous THF was still viable, but for further scale up it is difficult and expensive to procure
THF this dry. To alleviate this issue, experiments were done to show that increasing the
iPrMgCl charge would overcome this sensitivity. It was determined that after charging 2.2
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equivalents, an additional charge based on the HPLC area percent of remaining 3ꢀbromoꢀ2ꢀ
aminopyridine could be used to complete the metal halogen exchange. It was observed that
excess iPrMgCl led to poor conversion to the desired intermediate. This is presumably due to
deprotonation of 1ꢀBocꢀ4ꢀpiperdone which alters its primary electrophilic functional group.
The quench of the magnesium salt of the intermediate was initially done with 1N HCl and
saturated NH4Cl. This combination was used in an attempt to mitigate the likelihood of dropping
the pH too low and removing the Boc group used in the spirocycle formation. Unfortunately,
this quench led to solids throughout both layers which only dissolved after overnight age. The
pH continued to change throughout the dissolution of these solids making the pH ~ 7 target
difficult to hit. Optimization led to a 50% saturated NH4Cl quench which dissolved all solids
rapidly and allowed effective pH adjustment.
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The spirocycle formation was completed by charging KOtBu in THF to the organic layer after
the NH4Cl quench. This ring closure was not sensitive to residual water in the organic layer, and
the product could be isolated by direct filtration with < 1% losses after it precipitated as the
potassium salt. However, the slurry that developed during ring closure was particularly thick and
there were concerns with how the slurry would scale. The simple addition of 5 volumes of 2ꢀ
MeTHF allowed this slurry to mix, transfer, and filter well upon scaleꢀup. With this procedure in
place, two batches were executed successfully in the kilo labs to give 2.6 kg in > 99 LCAP.
Early development work on the Boc deprotection focused on using anhydrous HCl in various
organic solvents. This was initially attractive due to the direct isolation of the bisꢀHCl salt from
the reaction mixture. However, after screening various mixtures of MeOH, EtOH, and IPA with
anhydrous HCl it was evident that the slurries that were generated were too thick to scale
effectively. To overcome this, 12N HCl (aq) was added to a slurry of 7 in IPA to effect the
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deprotection and allow for the slurry’s properties to be amenable to scaleꢀup. The IPA still
afforded a direct isolation by filtration with ≤ 5% losses, but the small amount of water allowed
the slurry to stir, transfer, and filter easily. This conversion to aqueous HCl had the added
benefit of being more cost effective.
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The HCl charge was initially 15 equivalents. Attempts to optimize this charge showed 7
equivalents of 12N HCl caused the reaction to stall at about 45ꢀ50 % completion. Based on this
result and the 12ꢀ18 hour age times required when 15 equivalents of HCl were used, it was
determined that the initial charge was appropriate.
We used this deprotection to successfully execute two batches in the kilo labs to provide 3 -
2HCl (1.6 kg of free base 3 present) in > 99 LCAP. The weight percent of free base 3 in the
solids was typically 50ꢀ60% by HPLC. When the mass was corrected for this weight percent the
yield over the last two steps was 85ꢀ90%. It was hypothesized that the weight percent was due
not only to the bisꢀHCl salt, but also to 1 equivalent of KCl which would have originated from 7.
To evaluate this hypothesis, elemental analysis was done on 3 - 2HCl. (Table 1) The results
support the presence of two equivalents of HCl and one equivalent of KCl. These inorganics
were acceptable for the subsequent chemistry, and so were left as part of the final isolated solids.
However, if necessary, it is likely that an aqueous workup with pH adjustment could be used to
provide inorganicꢀfree neutral 3.
Table 1. Elemental Analysis of 3 - 2HCl
Element Expected wt% Measured wt%
C
H
N
36
4
33
4
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CONCLUSION
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A novel synthesis of spiro[1Hꢀpyrido[2,3ꢀd][1,3]oxazineꢀ4,4'ꢀpiperidine]ꢀ2ꢀone (3) as a bisꢀ
HCl salt has been discovered and optimized for scaleꢀup. The robust and simple synthesis has
allowed generation of 1.6 kg of 3 as a bisꢀHCl salt in 77% overall yield.
EXPERIMENTAL SECTION
All commercially available chemicals and solvents were used as received without any further
purification. The NMR spectra were acquired on a Bruker Avance spectrometer at frequencies of
400 and 500 MHz, respectively, in the solvents indicated. HPLC spectra were collected on an
Agilent 1100 or 1200 series instrument. LCAP is defined as the area percent purity as
determined by HPLC
Synthesis of tertꢀbutyl Nꢀ(3ꢀbromoꢀ2ꢀpyridyl)carbamate (5)
Reagent grade THF (8.6 L, 10 vol) was charged to a 50 L glass reactor under a nitrogen
atmosphere. Using an charging bag which docked to the reactor head, solid NaHMDS (2.01 kg,
10.94 mol, 2.2 equiv) was charged to the reactor and the batch was cooled to 0ꢀ5 °C. Solid 2ꢀ
bromoꢀ3ꢀaminopyridine (0.86 kg, 4.97 mol, 1.0 equiv) was introduced in portions under inert
conditions while maintaining a batch temperature below 15 °C. The charging port was rinsed
with fresh THF (0.43 L, 0.5 vol) and the batch was agitated for 10 minutes at 5ꢀ10 °C. A
prepared solution of Boc2O (1.41 kg, 6.46 mol, 1.3 equiv) in THF (0.43 L, 0.5 vol) was added
using dose control to maintain a batch temperature below 15 °C. The batch was agitated for at
least 1 hour at 15 ± 5 °C and was monitored by HPLC. The batch was cooled to ꢀ5 to 0 °C and
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using dose control, water (3.4 L, 4 vol) was added to the reaction while the batch temperature
was maintained below 20 °C. The batch was then pH adjusted to pH 7ꢀ7.5 with 6N hydrochloric
acid (2.9 L, 3.4 vol, as needed) using an inꢀline calibrated pH meter to monitor the adjustment.
After the batch was agitated for 10 minutes at 15 °C, an aqueous solution of saturated
ammonium chloride solution (3.4 L, 4 vol) was added below 25 °C and stirred for 5ꢀ10 minutes.
The final pH range was between 6.5ꢀ7.1. The layers were separated over 15ꢀ30 minutes and the
lower aqueous layer was drained to a waste drum. To remove minor particulates, a 5 micron
cartridge filter was used to filter the organic solution into a drum. The solution was distilled on a
rotary evaporator at 40ꢀ45 °C bath temperature (80ꢀ140 mBar) to the minimum stir volume, and
then nꢀheptane (4.0 L, 4.6 vol) was introduced. The mixture was transferred to a reactor and nꢀ
heptane (13.2 L, 15.3 vol) was added. The mixture was stirred for 15 hours at ambient
temperature, and then cooled to 0ꢀ5 °C. The product was collected on an Aurora filter and the
cake was washed with nꢀheptane (1.7 L, 2 vol), and dried under vacuum. The dried cake was 1.2
kg of tan solids at > 99 LCAP, and 95.3 wt%. After applying the weight percent 1.14 kg of 5
was present which was an 84% yield. 1H NMR (DMSO)ꢀd6 δ 9.32 (s,1H), 8.03 (dd, J =1.77, 4.54
Hz, 1H), 8.10 (dd, J = 1.77 Hz, 8.03 Hz, 1 H), 7.19 (dd, J = 4.54 Hz, 8.03 Hz, 1 H), 1.44 (s, 9H).
13C NMR (125 MHz, DMSOꢀd6) δ 28.37, 81.79, 109.51, 119.88, 141.14, 147.54, 148.85, 150.76.
HRMSꢀESI (m/z): [M+Na]+ Calcd for C10H13BrN2NaO2: 295.0053; found: 295.0081.
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Synthesis of (1ꢀtertꢀbutoxycarbonylꢀ2'ꢀoxoꢀspiro[piperidineꢀ4,4'ꢀpyrido[2,3ꢀd][1,3]oxazine]ꢀ1'ꢀ
yl)potassium (7)
Tertꢀbutyl Nꢀ(3ꢀbromoꢀ2ꢀpyridyl)carbamate, 5, (1.09 kg, 3.99 mol, 1.0 equiv) was charged to a
50 L reactor and diluted with anhydrous 2ꢀMeTHF (8.3L, 7.5 vol). The mixture was cooled to 0ꢀ
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5 °C and 2M iPrMgCl in THF (4.56 kg, 9.35 mol, 1.2 equiv) was dosed while maintaining a
batch temperature below 15 °C. The resultant solution was agitated for 10ꢀ15 minutes at 15 °C
and an aliquot was quenched into water to monitor anion formation by HPLC.
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A prepared solution of 1ꢀBocꢀ4ꢀpiperidone (0.97 kg, 4.88 mol, 1.2 equiv) in 2ꢀMeTHF (3.3 L,
3 vol) was dosed below 15 °C. The mixture was stirred for 30 minutes and monitored by HPLC
for reaction completion.
Upon reaction completion, 20 wt% NH4Cl solution (13 L, 11.8 vol,) was slowly added while
maintaining a batch temperature below 20 °C. The solution was agitated for about 30 minutes,
and then the layers were settled over 15 minutes. The bottom aqueous layer was removed to
waste. The top organic solution was filtered through a 5 micron cartridge filter and the clarified
solution was charged to a reactor and cooled to 0ꢀ5 °C. A 1M KOtBu solution in THF (5.5 kg,
6.1 mol, 1.5 equiv) was dosed while maintaining a batch temperature below 20 °C. Additional 2ꢀ
MeTHF (4.8 kg, 5 vol) was added to aid in mobility of the resultant precipitate. The slurry was
agitated over 15 hours at 20 °C and 7 was collected on an Aurora filter, and dried under vacuum.
After drying to < 10% volatiles by LOD, 1.78 kg of solids were isolated at > 99 LCAP. These
solids contained 1.43 kg (quantitative yield by HPLC assay) of (1ꢀtertꢀbutoxycarbonylꢀ2'ꢀoxoꢀ
spiro[piperidineꢀ4,4'ꢀpyrido[2,3ꢀd][1,3]oxazine]ꢀ1'ꢀyl)potassium.
1H NMR (DMSO)ꢀd6 δ 7.85 (dd, 1.80, 1H), 7.13 (dd, J = 1.80, 7.30 Hz, 1H), 6.41 (dd, J =
4.78, 7.30 Hz, 1H), 3.9 (m, 2 H), 3.12 (s, 2H), 1.75 (d, J = 12.01, 2 H), 1.64 (dt, J = 4.77, 12.01,
2H, 1.41 (s, 9 H). 13C NMR (125 MHz, DMSOꢀd6) δ 28.59, 35.57, 38.94 (bm), 80.17, 80.66,
119.46, 120.35, 132.32, 148.25, 148.30, 150.60, 154.79. HRMSꢀESI (m/z): [M+H]+ Calcd for
C16H22N3O4: 319.1532; found: 319.1528.
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Synthesis of spiro[1Hꢀpyrido[2,3ꢀd][1,3]oxazineꢀ4,4'ꢀpiperidine]ꢀ2ꢀone bisꢀHCl (3 - 2HCl)
(1ꢀtertꢀbutoxycarbonylꢀ2'ꢀoxoꢀspiro[piperidineꢀ4,4'ꢀpyrido[2,3ꢀd][1,3]oxazine]ꢀ1'ꢀ
yl)potassium, 7, (1.65 kg; adjusted wt: 1.27 kg, 3.98 mol) was charged to a reactor. Isopropyl
alcohol (10 kg, 12.7 L, 10 vol) was charged and the mixture was cooled to ꢀ5 to 0 °C.
Hydrochloric acid (12N, 6 L, 18 mol eq) was dosed while maintaining a batch temperature below
15 °C.
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The reaction was agitated over 12ꢀ18 hours at 15ꢀ20 °C. The process was monitored by HPLC
analysis for conversion. Upon complete conversion, the mixture was cooled to 0ꢀ5 °C, filtered
and dried under vacuum at ambient temperature to yield 1.38 kg of solids containing 3 as a bisꢀ
HCl salt with 1 equivalent of KCl (> 99 A%, 59.2 wt%, contains 0.816 kg 3 free base, 91.5%
yield).
1H NMR (DMSO)ꢀd6 δ 10.9 (s, 1H), 9.56 (bs, 1 H), 9.34 (bs, 1 H), 8.25 (dd, J = 1.59, J = 4.97
Hz, 1 H), 7.62 (dd, J = 1.59, J = 7.56 Hz, 1 H), 7.15 (dd, J = 4.97, J = 7.56 Hz, 1 H), 3.3 (d, J =
12.00, 2 H), 3.1 (q, J = 12.01, 2 H), 2.44 (dt, J = 4.72, J = 14.7 Hz, 2 H), 2.2 (d, J = 14.17 Hz, 2
H) 13C NMR (125 MHz, DMSOꢀd6) δ 31.37, 38.72, 77.35, 118.88, 119.17, 132.20, 147.86,
148.48, 149.27. HRMSꢀESI (m/z): [M+H]+ Calcd for C11H14N3O2: 219.1008; found: 219.1001.
ACKNOWLEDGMENT
We are grateful to Mark Olsen, and Chris Neville, for analytical support during the
development of this process. We would also like to thank Michael Christie, Partha Mudipalli,
Jing Fang, Russell Craig, and Steve Mangos for operations support during the development and
scale up of this process.
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