Synthesis of an ORL-1 Receptor Antagonist via a Radical Bromination and Deoxyfluorination to Afford a gem-Difluorospirocycle

Article abstract of DOI:10.1021/op5000094

The development of a synthesis of an ORL-1 receptor antagonist is described. The key process improvements in the synthetic sequence include a multikilogram bromination process and the development of a convergent coupling strategy. The process improvements resulted in the production of the active pharmaceutical ingredient (API) on a multikilogram scale.

Full text of DOI:10.1021/op5000094

Article
pubs.acs.org/OPRD
Synthesis of an ORL‑1 Receptor Antagonist via a Radical Bromination
and Deoxyfluorination to Afford a gem-Difluorospirocycle
Amy C. DeBaillie,*,† Chauncey D. Jones,† Nicholas A. Magnus,† Carlos Mateos,‡ Alicia Torrado,‡
James P. Wepsiec,† Ramachandar Tokala,§ and Prasad Raje§
†Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
‡Centro de Investigacion
́
Lilly, Avda. de la Industria 30, 28108-Alcobendas, Madrid, Spain
§Research and Development Group, Cambridge Major Laboratories, W130 N10497 Washington Drive, Germantown, Wisconsin
53022, United States
S
* Supporting Information
ABSTRACT: The development of a synthesis of an ORL-1 receptor antagonist is described. The key process improvements in
the synthetic sequence include a multikilogram bromination process and the development of a convergent coupling strategy. The
process improvements resulted in the production of the active pharmaceutical ingredient (API) on a multikilogram scale.
(4) under acidic conditions yielded the desired unprotected
spirocycle, (5), which was reprotected and chlorinated to give
spirocycle 6. The challenging gem-difluoro moiety was then
installed in three steps. A photochemical bromination of 6 with a
100 W bulb gave the benzylic bromide (7). Exposure of 7 to
Kornblum oxidation4 conditions gave a 1:1 mixture of the
secondary alcohol (8) and desired ketone (9). The mixture was
converted completely to 9 under TEMPO/NaClO conditions.5
Treatment of 9 with DeoxoFluor and removal of the Boc
protecting group gave the desired gem-difluorospirocycle, (10).
A reductive amination of 10 with aldehyde 11 cleanly gave
pyrazole 12, which was coupled6 with bromide 13 to yield
aldehyde 14 as a 9:1 mixture of regioisomers. The desired
regioisomer of 14 was isolated via chromatography and
subsequently reduced with sodium borohydride to provide 1.
While acceptable to deliver gram quantities of 1 for early
toxicological evaluations, a more scalable route for kilogram
quantities was desired. Specifically, alternative means to install
the gem-difluoro moiety as well as a regioselective synthesis of 1
would benefit the advancement of the program and enable the
delivery of material to fund additional studies.
INTRODUCTION
■
Nociceptin/orphanin FQ receptor antagonists, specifically
antagonists of the opioid receptor like-1 (ORL-1), have
demonstrated antidepressant activity and anorectic activity in
numerous studies with animal models for depression and feeding
behavior.1 As a result, ORL-1 antagonists are deemed to be useful
for the treatment of depression and/or the treatment of obesity.1
As part of our ongoing focus in neuroscience research, we were
interested in compounds of substructure A. Herein we describe
the development route used to produce kilogram quantities of
one such compound (1) of general formula A.
Process Development Synthesis. To accomplish the goal
of obtaining a regioselective synthesis of 1, it was envisioned that
aldehyde 15 and spirocycle 10 would be coupled via a reductive
amination where R would be either the alcohol or the ester
(Figure 1). The gem-difluorospirocycle (10) would be prepared
by a similar spiro-cyclization as described in Scheme 1 from 3 and
4.
The development efforts began by investigating the
spirocyclization of 3 and 4. It was quickly realized that 4 did
not need to be protected for the condensation with 3. The
unprotected spirocycle (5) was obtained in a 53% yield from 3
and 4-piperidone hydrochloride hydrate (16) (Scheme 2). This
RESULTS AND DISCUSSION
■
Discovery Chemistry Route. The discovery synthesis2 of 1
began with the reduction of commercially available 2-(thiophen-
3-yl)acetic acid (2) to yield 2-(thiophen-3-yl)alcohol (3)3
(Scheme 1). Condensation of 3 with Boc protected piperidone
Special Issue: Oxidation and Oxidative Reactions
Received: January 10, 2014
© XXXX American Chemical Society
A
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Scheme 1. Initial Route to ORL-1 Receptor Antagonist 1
Figure 1. Retrosynthetic Analysis of 1.
result was significant as it reduced the raw material costs, reduced
the campaign timeline by 1 week, and avoided the inefficient
reinstallation of the Boc protecting group. Further development
of the synthesis optimized the chlorination and protection steps
for kilogram scale to yield 39 kg of 6 as a single batch with 97.5%
B
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Scheme 2. Optimization of the Synthesis of 6
purity. With 6 in hand, the installation of the gem-difluoro moiety
was evaluated.
It was hypothesized that 6 could be directly converted to
ketone 9 via a benzylic oxidation (Figure 2), which would remove
the requirement to conduct a photochemical bromination on
scale and reduce the overall number of synthetic transformations.
Figure 3. Retrosynthesis of 17 from 6.
deprotonation (Scheme 3). The desired product, 18, was not
obtained; however, a 1:1 mixture of 19 and 20 was observed. To
prevent the formation of 19, n-BuLi was replaced with LiHMDS
and KOtBu. The experiment was repeated, and deuterium
incorporation was not detected with either base at −78 °C. In
light of these results and an approaching material delivery
requirement, efforts were refocused on developing the discovery
route to enable the production.
The radical bromination of 6 to yield 7 had been extensively
screened by the discovery group to find the best radical initiator
in combination with N-bromosuccinimide (NBS) (Table 2). It
was found that 2,2′-azobis(isobutyronitrile) (AIBN) and benzoyl
peroxide gave 7; however, the conditions did not yield
reproducible results (entries 1−3 and 5−7, respectively).
Photochemical bromination conditions with a 60 W bulb with
NBS yielded a consistent conversion to 7 from a 0.3 to 130 g scale
with additional charges of NBS (entries 8−10) needed for
acceptable conversion. As a result, these conditions with a 100 W
bulb were utilized to deliver gram quantities of 1.
Figure 2. Retrosynthesis of ketone 9.
Unfortunately, the literature conditions7 for benzylic
oxidations that were investigated within the short development
time frame, failed to cleanly yield the desired ketone, 9, as the
major product (Table 1).
Table 1. Conditions Investigated for the Benzylic Oxidation
of 6
reaction conditions
result
N-hydroxyphthalimide, CH3CN, O2 (400 unreacted starting material (6)
psi), 80 °C8
NaClO2, N-hydroxyphthalimide, H2O,
CH3CN, 50 °C9
decomposition
NaClO2, t-BuOOH, H2O, CH3CN, 50
unreacted starting material (6)
°C9
FeCl3·6H2O, t-BuOOH, pyridine, 50 °C10 mixture of ketone (9), starting
material (6), and secondary
alcohol (8)
KMnO4, Bu4NBr, 50 °C, H2O11
CrO3, t-BuOOH12
unreacted starting material (6)
mixture of ketone (9), starting
material (6), and impurities
DDQ, 1,4-dioxane, H2O, AcOH, 80 °C13 deprotection of 6
RuCl3·H2O, t-BuOOH, CH3CN, 80 °C14 mixture of ketone (9), starting
material (6), and impurities
Due to the challenges of conducting batch photochemical
reactions at scale,16,17 the conditions to conduct a thermally
induced radical bromination were reevaluated. It was determined
that 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (0.8 equiv)
in the presence of either 2,2′-azobis(2,4-dimethyl-valeronitrile)
(Vazo-52, 0.05 equiv) or AIBN (0.06 equiv) would lead to
complete consumption of 6 to give bromide 7. AIBN (0.07
equiv) was selected for scale-up due to its availability in bulk and
ease of handling in comparison to Vazo-52.18 The optimized
process was to add AIBN to a slurry of 6 and 21 (DBDMH) in
CH2Cl2 (Scheme 4). The suspension was heated at 40 °C for 5 h
before quenching with an aqueous solution of sodium bisulfite.
Since development efforts did not yield a process to isolate 7
without chromatography and significant yield loss, it was
telescoped directly into the subsequent step after solvent
Bi2O3, NaBH4, pyridine, 2-
pyridinecarboxylic acid, CH3COOH, t-
BuOOH, 100 °C15
mixture of ketone (9), starting
material (6), and impurities
It was found that either unreacted starting material (6) was
isolated with trace amounts of ketone (9) detected by HPLC and
LCMS or decomposition occurred. As a result, another proposal
was explored in an attempt to replace the benzylic bromination
step. It was envisioned that 17 could be synthesized directly from
6 via deprotonation and treatment with an electrophilic fluorine
source (Figure 3). If this idea proved to be successful, two
synthetic steps could be removed from the synthesis.
To probe this route proposal, 6 was treated with n-BuLi at −78
°C and quenched with MeOD to determine the site of
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Scheme 3. Deuterium Quenching Results
10, DeoxoFluor was utilized to install the gem-difluoro moiety in
a 62% yield.21 The Boc protecting group was cleaved under
anhydrous acidic conditions at 50 °C to give 7.5 kg of 10 in an
88% yield as the HCl salt directly from the reaction conditions
upon cooling.
Table 2. Benzylic Bromination Results for the Conversion of 6
to 7
radical
T
(°C)
a
entry
1
initiator
NBS (equiv)
1.5
scale
result
AIBN
70
70
100
70
70
70
70
50
40
40
3 g 90%
With a process in place to prepare 10, the final steps of the
synthesis of 1 were evaluated with the goal of developing a route
that would prevent the formation of regioisomers. It was
envisioned that this goal could be accomplished by installing the
pyrazole moiety via a reductive amination between 10 and 15
(Figure 1). This proposal required the development of a
synthesis of 15 where R is the primary alcohol or the ester. Initial
studies focused on the SNAr of 22 with 11 to yield 23 as a single
isomer either via purification or a regioselective synthesis. After a
brief screen of bases, solvents, and temperatures, it was
concluded that the ideal conditions were 2.0 equiv of K2CO3,
0.1 equiv of KI, and 5 volumes of DMF at 100 °C. These
conditions gave 23 in a 72% yield as a single isomer via
crystallization from the reaction solution with water (Scheme
5).22 Recrystallization from IPA provided an increase in the
purity (97.4% to 99.7%). This process afforded 9.5 kg of ester 23.
conversion
0.3 g multiple
products
0.3 g multiple
products
0.3 g multiple
products
0.26 g 96%
conversion
3 g 95%
conversion
45 g 80%
conversion
0.3 g 96%
conversion
5 g 95%
conversion
130 g 94%
conversion
2
3
AIBN
AIBN
AIBN
2
1.5
b
4
1.5
5
benzoyl
peroxide
1.5
6
benzoyl
peroxide
1.5
7
benzoyl
peroxide
1.5
8
60 W bulb
60 W bulb
60 W bulb
1.1 + 0.25
1.1 + 0.25
1.1 + 025 + 0.1
9
10
a
b
Conversion as determined by HPLC area %. CH3CN was used as
Scheme 5. Synthesis of 23
the reaction solvent. All other entries utilized chlorobenzene as the
reaction solvent.
exchanging from CH2Cl2 into DMSO. These conditions gave 7
on a kilogram scale with an HPLC purity of 57%.19 Oxidation of
7 under Kornblum conditions with sodium bicarbonate (2.5
equiv) at 50 °C gave a mixture of secondary alcohol 8 and ketone
9.20 This mixture was exposed to a TEMPO/NaClO oxidation to
yield 11 kg of 9 with 91% purity as a yellow solid in a 40% yield
over three steps. To convert ketone 9 to gem-difluorospirocycle,
Scheme 4. Optimized Synthesis of 10
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Scheme 6. Completion of the Synthesis of 1
With 23 in hand as a single isomer the reductive amination
with 10 and subsequent reduction of the ester to afford 1 was
evaluated (Scheme 6). Amine 10 was freebased with NaOH and
used directly as a solution in THF in the reductive amination with
24 and NaBH(OAc)3. The reaction gave 7.8 kg of 24 in an 83%
yield as the freebase after neutralization with NaHCO3 and
crystallization from IPA. To complete the synthesis of 1, the ethyl
ester moiety of 24 needed to be reduced to the primary alcohol.
The discovery route (Scheme 1) cleanly reduced an aldehyde
with NaBH4 at this stage of the synthesis; however, the reduction
of the ethyl ester proved to be quite challenging. Reducing
agents23 such as lithium or sodium borohydride, diisobutylalu-
minum hydride, and vitride gave minimal product formation
even after excess reagent was employed. The best results were
obtained with 3 equiv of lithium triethylborohydride (Super-
Hydride) at −20 to −15 °C. These conditions were scaled to
deliver 5.78 kg of 1 that did not pass the residual boron
specification. To remove the boron residue, 1 was slurried in 10
volumes of water for 4 h, filtered, and recrystallized from 10
volumes of IPA to yield 4.19 kg of 1 that passed the residual
boron specification in a 59% yield with >98% purity.
μm; Flow: 1.0 mL/min; A: 0.1% H3PO4 in H2O; B: CH3CN;
Run time: 20 min; Gradient: 20% B to 80% B over 12 min and
hold for 3 min; 80% B to 20% B in 0.2 min and hold for 4 min;
Column Temperature: 30 °C; Wavelength: 245 nm. HPLC
method for the analysis of compounds 10, 23, 24, and 1:
Column: Ascentis Express C18, 150 mm × 4.6 mm, 2.7 μm;
Flow: 1.0 mL/min; A: 0.1% TFA in H2O, B: 0.05% TFA in
CH3CN. Gradient: 5% B to 60% B over 20 min; 60% B to 95% B
over 1 min and hold for 5 min; 95% B to 5% B in 0.1 min and hold
for 8 min; Column Temperature: 40 °C; Wavelength: 245 nm.
4′,5′-Dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] (5).
A 12.8 wt % solution of 2-(thiophen-3-yl)ethan-1-ol, 3 (32.0 kg,
249.6 mol) in CH2Cl2 (218.3 kg, 164 L) was treated with 4 Å
molecular sieves (6.5 kg) to reach a KF specification of <0.05%.
The mixture was filtered and washed with CH2Cl2 (32.0 kg, 24
L). Piperidone hydrochloride hydrate, 16 (38.3 kg, 249.3 mol),
was added to the filtrate, and the mixture was cooled to 0−5 °C.
Trifluoroacetic acid (107.0 kg, 938.6 mol) was added at a rate to
maintain the internal temperature below 10 °C. After the
addition was complete, the reaction was heated to 20−25 °C
until 2-(thiophen-3-yl)ethan-1-ol was <15% as determined by
GC (37 h). The mixture was concentrated, and MTBE (236.8 kg,
320 L) was added. The resulting slurry was cooled to 0−5 °C and
stirred for 1 h. The slurry was filtered, and the wet cake was dried
at 30 °C at 460 Torr. The cake was then treated with purified
water (192.0 kg, 192 L) and heated to 40−45 °C until a
homogeneous solution was obtained. A 19% aqueous solution of
sodium hydroxide (157.4 kg) was added to obtain a pH > 11. The
mixture was cooled to 0−5 °C and held for 2 h. The resulting
slurry was filtered, and the wet cake was dried at 40−45 °C to
yield 27.9 kg of 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-
c]pyran], 5, as a light-yellow solid in a 53% yield with a 98.5%
CONCLUSION
■
In summary, a synthesis of 1 has been developed. The final
process was demonstrated on a kilogram scale to produce 4 kg of
1 with >98% purity. Key improvements were the development of
a multikilogram radical bromination process with AIBN and
dibromodimethylhydantoin and a convergent coupling strategy
that eliminated the use of copper, an expensive diamine ligand,
and the formation of regioisomers.
EXPERIMENTAL SECTION
1
area purity. H NMR data see ref 2c. 13C NMR (100 MHz,
■
CDCl3): 132.8, 126.8, 122.5, 73.0, 59.2, 41.3, 38.1, 26.5.
General. Analytical methods: GC method to monitor the
synthesis of 5: Column: HP-5, 30 m length × 0.32 mm ID × 0.25
μm film or column equivalent. Carrier gas: Helium; Flow rate:
1.90 mL/min. Detector Temperature: 300 °C; Run Time: 22.5
min; Injection volume: 1 μL. Diluents: CH2Cl2 or MeOH with a
sample concentration of 4.0 mg/mL. Temperature Program:
Initial temp: 50 °C (On) Initial time: 2.00 min; Ramp rate: 20.00;
Final temp: 260 °C; Final time: 10 min. HPLC method for the
analysis of 5: Column: Waters Symmetry C18, 4.6 mm × 150
mm, 3.5 μm; Flow: 1.0 mL/min; A: 0.1% H3PO4 in H2O; B:
CH3CN; Run time: 25 min; Gradient: 5% B to 60% B over 15
min; 60% B to 90% B over 20 min. Change back to 5% B over 0.1
min and hold for 4 min. Column Temperature: 30 °C; Injection
volume: 5 μL; Wavelength: 230 nm; Sample concentration: 0.5
mg/mL. HPLC method for the analysis of compounds 6-Boc
protected 10: Column: Zorbax SB-C8, 4.6 mm × 75 mm, 3.5
tert-Butyl 2′-chloro-4′,5′-dihydrospiro[piperidine-4,7′-
thieno[2,3-c]pyran]-1-carboxylate (6). Step 2a: A mixture of
MTBE (165.5 kg, 223 L), 5, (27.9 kg, 133.3 mol), 4-
dimethylaminopyridine (0.8 kg, 6.5 mol), and triethylamine
(14.8 kg, 20 L, 146.2 mol) was cooled to 0−5 °C. A solution of di-
tert-butyl dicarbonate (30.4 kg, 139.9 mol) in MTBE (37 kg, 50
L) was then added at a rate of 10−15 kg/h. The mixture was
stirred at 0−5 °C and deemed complete when <2% of 5 remained
by HPLC (3.5 h). The reaction was quenched with conc. HCl
(16.5 kg) in H2O (153.8 kg, 153.8 L). The layers were separated,
and the organic phase was washed with H2O (139.5 kg, 139.5 L)
and 20% brine (139.5 kg). The organic phase was concentrated
until 50−80 L of the mixture remained. The solvent was
exchanged by adding CH3CN (37 kg, 47 L) and reducing the
volume to 50 L. CH3CN (37 kg, 47 L) was added, and the
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volume was again reduced to 50 L at 310 Torr. The solution was
then diluted with CH3CN (226 kg, 288 L) and used directly in
the next step. A 100% yield was assumed of the Step 2a product.
Step 2b: To the CH3CN solution of Step 2a was added 4-
dimethylaminopyridine (0.8 kg, 6.5 mol) and N-chlorosuccini-
mide (26.7 kg, 200 mol). The mixture was heated to 65−72 °C
until the product from Step 2a was <1% by HPLC (4 h). The
reaction was cooled to 40−50 °C and quenched with an aqueous
solution of sodium bisulfite (13.9 kg in 138.6 L of H2O). Seed
crystals of 6 (0.281 kg) were added after the solution had reached
20−30 °C. The thin slurry was held at 1 h, and then H2O (138.6
kg, 138.6 L) was added. The resulting slurry was cooled to 0−5
°C and held for 12.5 h. The mixture was filtered, and the cake was
rinsed with a 10 °C solution of H2O (21 kg, 21 L) and CH3CN
(10 kg, 13 L). The filter cake was dried at 40−45 °C until the
H2O content was ≤0.2%. tert-Butyl 2′-chloro-4′,5′-dihydrospiro-
[piperidine-4,7′-thieno[2,3-c]pyran]-1-carboxylate, 6, was iso-
lated as a light yellow solid (31.5 kg, 69% yield over two steps,
97.5% area purity, 80.8 wt %. 1H NMR (400 MHz, DMSO-d6):
6.83 (s, 1H), 3.85−3.76 (m, 4H), 3.09−2.88 (m, 2H), 2.53 (t, J =
5.2 Hz, 2H), 1.94−1.88 (m, 2H), 1.54 (dt, J = 4.8, 13.2 Hz, 2H),
1.38 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 154.3, 140.7,
133.6, 127.2, 126.6, 79.2, 72.1, 59.0, 37.6, 28.5, 26.1.
tert-Butyl 4′-bromo-2′-chloro-4′,5′-dihydrospiro-
[piperidine-4,7′-thieno[2,3-c]pyran]-1-carboxylate (7). CAU-
TION: Appropriate safety data should be collected prior to
conducting this reaction at scale. CH2Cl2 (458 kg, 344 L), 6
(38.4 kg, 111.7 mol), 1,3-dibromo-5,5-dimethylhydantoin (25.8
kg, 90.2 mol), and 2, 2′-azobis(2-methylpropinitrile (1.2 kg, 7.3
mol) were heated to 35−45 °C until <5% of 6 remained by
HPLC (5 h). The reaction was quenched with aqueous sodium
bisulfite (11.5 kg in 180.5 L of H2O). The layers were separated,
and the organic layer was concentrated to 60−100 L. The
resulting mixture was filtered through silica gel (38.4 kg). The
silica plug was rinsed with petroleum ether (25.7 kg × 3, 120 L)
and CH2Cl2 (919 kg, 690 L). The organic phase was
concentrated (T ≤ 30 °C, P ≤ 310 Torr) until 60−100 L
remained. DMSO (262 kg, 238 L) was added and the mixture
was stirred until the solution became homogeneous. tert-Butyl 4′-
bromo-2′-chloro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-
c]pyran]-1-carboxylate, 7, proved to be unstable to isolation due
to the ability to easily hydrolyze to alcohol 8. Therefore, it was
stored as a solution in DMSO and used without further
purification. The yield was assumed to be 100%, and the purity
was determined to be 57.3% by HPLC.19 1H NMR (400 MHz,
DMSO-d6): 7.01 (s, 1H), 5.34 (t, J = 2.4 Hz, 2H), 4.21 (dd, J =
2.8, 13.6 Hz, 1H), 4.02 (dd, J = 2.4, 13.6 Hz, 1H), 3.90−3.74 (m,
2H), 3.14−2.84 (m, 2H), 2.22−2.06 (m, 1H), 1.91−1.84 (m,
1H), 1.69 (dt, J = 4.8, 12.8 Hz, 1H), 1.48 (dt, J = 4.8, 14.0 Hz,
1H), 1.38 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 154.2,
143.4, 134.3, 127.9, 126.8, 79.3, 73.0, 65.7, 43.0, 38.7, 35.1, 28.5.
tert-Butyl-2′-chloro-4′-oxo-4′,5′-dihydrospiro[piperidine-
4,7′-thieno[2,3-c]pyran]-1-carboxylate (9). NaHCO3 (23.4 kg,
278.6 mol) was added to a solution of 7 (47.2 kg, 111.6 mol) in
DMSO. The mixture was heated to 48−52 °C until 7 was <1% by
HPLC (16 h). H2O (192 kg, 192 L) was added, and the mixture
was cooled to 15−25 °C. CH2Cl2 (407 kg, 306 L) was added, and
the layers were separated. The organic phase was washed with
H2O (192 kg, 192 L), and the aqueous phases were back
extracted with CH2Cl2 (102 kg, 76 L). To the combined organic
phase was added 6% NaHCO3 (191.9 kg) and KBr (4.0 kg, 33.6
mol). The mixture was cooled to −5−0 °C, and then 2,2,6,6-
tetramethylpiperidinooxy (0.9 kg, 5.75 mol) and a solution of
NaClO (8.3 kg, 111.5 mol) were added. The biphasic mixture
was stirred for 1 h. The layers were separated, and the aqueous
was back extracted with CH2Cl2 (51 kg, 38 L). The combined
organic phase was reexposed to the oxidation conditions. To the
combined organic phase was added 6% NaHCO3 (191.9 kg) and
KBr (4.0 kg, 33.6 mol). The mixture was cooled to −5−0 °C, and
then 2,2,6,6-tetramethylpiperidinooxy (0.9 kg, 5.75 mol) and a
solution of NaClO (8.3 kg, 111.5 mol) were added. The reaction
was quenched with 6% aqueous solution of sodium bisulfite (96.3
kg). The layers were separated, and the aqueous phase was
extracted with CH2Cl2 (50 kg, 37.5 L). The combined organic
phases were concentrated to dryness (T ≤ 35 °C, P ≤ 310 Torr).
CH3CN (31 kg, 34 L) was added, and the solution was
concentrated to dryness. This was repeated two times. CH3CN
(7.6 kg, 9.7 L) was added to the residue. The solution was cooled
to −10−0 °C and stirred for 6 h. The resulting slurry was filtered,
and the wet cake was dried at 40−45 °C until the H2O content
was <0.10%. 16.1 kg (40% over three steps) of tert-butyl 2′-
chloro-4′-oxo-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]-
pyran]-1-carboxylate, 9, was isolated as a yellow solid with 90.8%
area purity by HPLC. 1H NMR (400 MHz, DMSO-d6): 7.31 (s,
1H), 4.38 (s, 2H), 3.90−3.80 (m, 2H), 3.13−2.88 (m, 2H),
2.18−2.15 (m, 2H), 1.73 (dt, J = 4.8, 13.6 Hz, 2H), 1.38 (s, 9H).
13C NMR (100 MHz, DMSO-d6): 187.9, 160.1, 154.2, 133.3,
129.7, 123.2, 79.4, 73.3, 67.0, 35.3, 28.5.
2′-Chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-
thieno[2,3-c]pyran] Hydrochloride (10). CAUTION: Appro-
priate safety data and compatibility of bis(2-methoxyethyl)-
aminosulfur trifluoride with the selected equipment should be
collected prior to conducting this reaction at scale.24 A mixture of
toluene (19.5 kg, 22.5 L), 9 (15.0 kg, 41.9 mol), and bis(2-
methoxyethyl)aminosulfur trifluoride (23.9 kg, 108 mol) was
heated to 68- 72 °C until 9 was <15% by HPLC (21 h). The
mixture was then cooled to 25−35 °C and diluted with CH2Cl2
(149 kg, 112 L). An aqueous solution of NaHCO3 (24.0 kg in
360 L of H2O) was then added, and then layers were separated.
The aqueous layer was extracted with CH2Cl2 (99.4 kg × 2 (74.7
L)), and the combined organic phases were concentrated to 15 L
(T ≤ 35 °C, P ≤ 310 Torr).
The resulting residue was purified via column chromatography
with a solvent system of petroleum ether (804 kg, 1256 L),
CH2Cl2 (54 kg, 41 L) and MTBE (31 kg, 42 L) to obtain 9.8 kg
(62% yield) of Boc protected 102a in 94.8% area purity by HPLC.
IPA (56.3 kg, 71.6 L) at 0−5 °C was added to acetyl chloride
(134.6 mol, 10.6 kg) followed by Boc protected 10 (10.2 kg, 26.9
mol). The suspension was heated at 50−55 °C for 1−2 h or until
Boc protected 10 was <1.0% by HPLC. The slurry was then
cooled to 0−5 °C from 50 °C over 1 h and held for 2 h. The
resulting slurry was filtered, and the wet cake was washed with
IPA (two times, 8.0 kg, 10.2 L) and vacuum-dried at 30 °C. A
quantity of 7.49 kg (88%) of 2′-chloro-4′,4′-difluoro-4′,5′-
dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] hydrochlor-
ide, 10, was isolated as a white solid with 97.9% purity by
1
HPLC. For H NMR and HRMS see ref 2a. 13C NMR (75.4
MHz, DMSO-d6): 147.0, 146.9, 146.8, 129.9, 129.3, 128.9, 128.6
122.5, 116.2, 113.0, 109.8, 71.9, 64.0, 63.5, 63.1, 32.2.
Ethyl 2-(4-Formyl-3-methyl-1H-pyrazol-1-yl)nicotinate
(23). A mixture of DMF (27.6 kg, 29.2 L), 22 (5.85 kg, 31.5
mol), K2CO3 (8.7 kg, 63.0 mol), and KI (0.5 kg, 3.15 mol) were
purged with nitrogen for 1 h. 11 (5.2 kg, 47.3 mol) was added,
and the mixture was warmed to 95−100 °C over 2 h and held for
6 h or until 22 was <4% by HPLC. The mixture was cooled to 0−
5 °C and quenched with H2O (87.7 kg, 87.7 L). The resulting
F
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slurry was filtered. The wet cake was washed with H2O (29.2 kg,
29.2 L) and heptane (20.0 kg, 29.2 L) and vacuum-dried at 40 °C
at P ≤ 10 Torr to yield 5.97 kg (72%) of ethyl 2-(4-formyl-3-
methyl-1H-pyrazol-1-yl)nicotinate, 23, as a brown solid. To
recrystallize crude 23, CH2Cl2 (299.8 kg, 226.3 L), crude 23
(11.3 kg), MgSO4 (3.4 kg), and charcoal (0.6 kg) were slurried
for 1 h. The slurry was filtered, and the cake was washed with
CH2Cl2 (60.0 kg, 45.3 L). The filtrate was concentrated to 3−5
volumes. IPA (88.8 kg, 113.1 L) was charged to the residue, and
the volume was reduced to 3−5 volumes. IPA (88.8 kg, 113.1 L)
was charged again to the residue, and the volume was reduced to
3−5 volumes. IPA (88.8 kg, 113.1 L) was charged to the residue,
and the slurry was heated to 78−83 °C to obtain a homogeneous
solution. The solution was cooled to −5−0 °C over 3 h and held
for 12 h. The solids were filtered. The wet cake was washed with 0
°C IPA (8.9 kg, 11.3 L) and vacuum (P ≤ 10 Torr) dried at 45 °C
to yield 9.51 kg (84%) of ethyl 2-(4-formyl-3-methyl-1H-
pyrazol-1-yl)nicotinate, 23, as a light-tan solid with 97.5% purity
by HPLC. 1H NMR (300 MHz, CDCl3): 10.02 (s, 1H), 8.82 (s,
1H), 8.56 (d, J = 8 Hz, 1H), 8.01 (d, J = 8 Hz, 1H), 7.38 (t, J = 8
Hz, 1H), 4.25 (q, J = 12 Hz, 2H), 2.45 (s, 3H), 1.25 (t, J = 12 Hz,
3H). 13C NMR (75 MHz, DMSO-d6): 185.6, 165.9, 150.4, 150.2,
146.5, 139.2, 135.7, 123.2, 122.5, 121.4, 61.5, 13.6, 12.9.
Ethyl 2-(4-((2′-Chloro-4′,4′-difluoro-4′,5′-dihydrospiro-
[piperidine-4,7′-thieno[2,3-c]pyran]-yl)methyl)-3-methyl-1H-
pyrazol-1-yl)nicotinate (24). A slurry of THF (50.5 kg, 56.9 L)
and 10 (56.9 kg, 18.0 mol) was cooled to 0−5 °C. NaOH (4 N,
2.9 kg, 35.9 mol, in 7.1 L of H2O) was added at a rate to maintain
the internal temperature between 0−5 °C (20 min). After stirring
for 2 h, the layers were separated. To the organic layer was
charged Na2SO4 (5.7 kg), and the slurry was stirred for 2 h. The
organic layer was filtered, and the cake was washed with THF
(30.3 kg, 34.1 L). The organic layer was concentrated to 3−5
volumes. THF (30.3 kg, 34.1 L) was added to the residue, and the
volume was reduced to 3−5 volumes. The process was repeated
two times to obtain a KF < 0.1%. 23 (46.6 kg, 18.0 mol) was then
added to the THF solution. The solution was cooled to 0−5 °C,
and NaBH(OAc)3 (7.6 kg, 36.0 mol) was added portionwise over
60−90 min. The mixture was warmed to 15−25 °C and stirred
for 20 h or until 10 was <3.0% by HPLC. The mixture was then
cooled to 0−5 °C and quenched with NaHCO3 (2.8 kg in 56.9 L
of H2O). EtOAc (51.3 kg, 56.9 L) was added, and the layers were
separated. The organic phase was washed with H2O (56.9 kg,
56.9 L) and a 20% NaCl solution (14.2 kg in 56.9 L of H2O). The
organic phase was concentrated to 3−5 volumes. IPA (22.3 kg,
28.4 L) was charged to the residue, and the volume was reduced
again to 3−5 volumes. IPA (44.6 kg, 56.9 L) was added, and the
slurry was heated to 78−82 °C to obtain a homogeneous
solution. The solution was then cooled to 15−20 °C over 3−6 h
and then cooled to −5−0 °C and held for 2 h. The resulting
slurry was filtered, and the wet cake was washed with IPA (8.9 kg,
11.4 L) and vacuum (P ≤ 10 Torr) dried at 45 °C. Ethyl 2-(4-
((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-
thieno[2,3-c]pyran]-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-
nicotinate, 24, (77.9 kg (83%)) was isolated as an off-white to tan
solid with 98.3% purity by HPLC. 1H NMR (400 MHz, CDCl3):
8.45 (dd, J = 1.6, 4.8 Hz, 1H), 8.40 (s, 1H), 7.85 (dd, J = 1.6, 7.6
Hz, 1H), 7.20 (dd, J = 5.2, 7.6 Hz, 1H), 6.93 (s, 1H), 4.33 (q, J =
7.2 Hz, 2 H), 3.99 (t, J = 10.4 Hz, 2H), 3.6 (bs, 2 H), 2.9 (bs, 2
H), 2.5 (bs, 2H), 2.27 (s, 3H), 2.11−2.08 (m, 4 H), 1.27 (t, J =
8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): 167.4, 151.0, 149.3,
147.8, 138.2, 130.1, 129.2, 129.0, 128.7, 121.8, 120.7, 114.0,
112.6, 110.9, 73.2, 64.4, 64.1, 63.8, 61.8, 51.5, 48.1, 36.0, 13.9,
12.3.
(2-(4-((2′-Chloro-4′,4′-difluoro-4′,5′-dihydrospiro-
[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-
1H-pyrazol-1-yl)pyridin-3-yl)methanol (1). A mixture of THF
(103.6 kg, 116.5 L) and 24 (77.7 kg, 14.8 mol) was cooled to −20
to −15 °C. The first equiv of Super-Hydride (1.0 M in THF, 14.9
L, 14.8 mol) was charged at a rate to maintain the internal
temperature between −20 to −15 °C (30 min). After stirring at
−20 to −15 °C for 45−60 min, the second equiv of Super-
Hydride (1.0 M in THF, 14.9 L, 14.8 mol) was charged to the
reaction mixture at a rate to maintain the internal temperature of
−20 to −15 °C (60 min). The reaction mixture was then stirred
at −20 to −15 °C for an additional 45−60 min before the third
equiv of Super-Hydride (1.0 M in THF, 14.9 L, 14.8 mol) was
added over a period of 60 min to the reaction mixture. The
reaction mixture was then sampled after stirring at −20 to −15
°C for 45−60 min and deemed complete when <4% of 24
remained. The reaction was quenched with EtOH (200 proof,
3.1 kg, 3.9 L), and the mixture was stirred at −20 to −15 °C for 1
h. A 15% NH4Cl solution (11.7 kg in 77.7 L of H2O) was added,
and the mixture was warmed to 15 to 25 °C. The mixture was
diluted with EtOAc (70.1 kg, 77.7 L), and the layers were
separated. The aqueous layer was extracted with EtOAc (70.1 kg,
77.7 L), and the combined organic phases were washed with a
NaCl solution (19.4 kg in 77.7 L of H2O), dried over MgSO4 (3.1
kg), and treated with charcoal (0.5 kg). After filtration, the
organic layer was concentrated to 2−3 volumes. IPA (61.0 kg,
77.7 L) was charged, and the volume was reduced to 3−5
volumes. IPA (12.2 kg, 15.5 L) was charged to the residue, and
the slurry was heated to 78−82 °C to obtain a homogeneous
solution. Heptane (53.1 kg, 77.7 L) was charged, and the solution
was cooled to 15−20 °C over 14 h. The resulting slurry was
further cooled to −5−0 °C and held for 2 h. The slurry was
filtered, and the wet cake was washed with heptane (10.6 kg, 15.5
L) and vacuum-dried at 45 °C to afford 6.14 kg of 1. To
recrystallize 1, a slurry of IPA (48.2 kg, 61.4 L) and crude 1 (6.14
kg) were heated to 78−82 °C to obtain a homogeneous solution.
The solution was then cooled to 15−20 °C over 3 h. The
resulting slurry was further cooled to −5−0 °C and held for 3 h.
The slurry was filtered, and the wet cake was washed with 0 °C
IPA (4.8 kg, 6.1 L) and vacuum (P ≤ 10 Torr) dried at 45 °C to
yield 5.78 kg of 1, which did not pass the residual boron
specification. A slurry of H2O (57.8 kg, 57.8 L) and 1 (5.78 kg)
was stirred at 15−30 °C for 4 h. The slurry was filtered, and the
wet cake was washed with H2O (17.3 kg, 17.3 L) and vacuum-
dried at 45 °C to afford 4.73 kg of 1. This material was further
purified via recrystallization from 10 vol of IPA to yield 4.19 kg
(59%) of (2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro-
[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-
1H-pyrazol-1-yl)pyridin-3-yl)methanol, 1, as a yellow solid with
98.7% purity. 1H NMR (500 MHz, CDCl3): 8.40 (s, 1H), 8.36
(dd, J = 1.8, 4.8 Hz, 1H), 7.75 (dd, J = 1.8, 7.5 Hz, 1H), 7.17 (dd, J
= 4.8, 7.5 Hz, 1H), 6.95 (s, 1H), 6.04 (t, J = 7.6 Hz, 1H), 4.66 (d, J
= 7.6 Hz, 2H), 4.04 (t, J = 10.3 Hz, 2H), 3.47 (s, 2H), 2.78 (d, J =
11.3 Hz, 2H), 2.40 (dd, J = 11.0, 11.3 Hz, 2H), 2.35 (s, 3H), 2.08
(dd, J = 11.0, 14.2 Hz, 2H) 1.86 (dd, J = 14.2 Hz, 2H). 13C NMR
(100 MHz, DMSO-d6): 149.9, 149.0, 147.8, 146.1, 138.1, 129.6,
129.2, 128.8, 128.6, 128.5, 128.2, 122.3, 121.8, 116.9, 115.7,
113.3, 110.9, 73.4, 63.4, 63.1, 62.8, 59.8, 51.0, 47.9, 36.2, 12.0.
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(19) Compound 7 was later determined to not be stable to the HPLC
conditions utilized. Further method development is needed to
determine the purity of this compound for a future campaign.
(20) It is hypothesized that the secondary alcohol is formed from the
hydrolysis of the alkoxysulfonium ylide. Compound 7 is also easily
hydrolyzed to alcohol 8 under the HPLC conditions.
ASSOCIATED CONTENT
* Supporting Information
Structure proof for compound 23. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
(21) After the completion of this work, reports of more desirable
deoxofluorinating reagents have been reported see: (a) Umemoto, T.;
Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199.
(b) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.;
LaFlamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050. (c) L’Heureux,
A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; LaFlamme, F.;
Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem.
2010, 75, 3401. Continuous processes have also been developed see:
Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetradehron 2009,
65, 6611. and Negi, D. S.; Koppling, L.; Lovis, K.; Abdallah, R.; Geisler,
J.; Budde, U. Org. Process Res. Dev. 2008, 12, 345.
(22) NMR data confirming the desired isomer was obtained is
provided in the Supporting Information.
(23) For a review see: Magano, J.; Dunetz, J. Org. Process Res. Dev.
2012, 16, 1156.
(24) Although, bis(2-methoxyethyl)aminosulfur trifluoride has been
reported to be more thermally stable than DAST, the appropriate safety
precautions should be taken. Bis(2-methoxyethyl)aminosulfur trifluor-
ide is a fuming liquid that is difficult to handle in humid environments,
reacts violently with water, and generates HF. HF is very toxic, corrosive,
and readily etches glass.
AUTHOR INFORMATION
Corresponding Author
*Telephone: 317-277-4298. E-mail: debaillie_amy_c@lilly.com.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Lisa Zollars for the confirmation
of structure for ester 23.
REFERENCES
■
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H
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