Process development and scale-up of a β-secretase inhibitor via a stereospecific jocic reaction

Article abstract of DOI:10.1021/op400115g

A scalable process for the synthesis of a spiropiperidine β-secretase inhibitor is described. Key stereochemical transformations utilized are a diastereoselective trichloromethyl addition followed by an unprecedented stereospecific Jocic reaction with an aniline nucleophile. Simplified processing was developed for a Dieckmann cyclization/decarboxylation sequence to give a process suitable for the production of kilogram quantities of API.

Full text of DOI:10.1021/op400115g

Article
pubs.acs.org/OPRD
Process Development and Scale-up of a β‑Secretase Inhibitor via a
Stereospecific Jocic Reaction
Kevin E. Henegar,* Ricardo Lira, Hui Kim, and Juan Gonzalez-Hernandez
Pfizer Global Research and Development, Groton Laboratories Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A scalable process for the synthesis of a spiropiperidine β-secretase inhibitor is described. Key stereochemical
transformations utilized are a diastereoselective trichloromethyl addition followed by an unprecedented stereospecific Jocic
reaction with an aniline nucleophile. Simplified processing was developed for a Dieckmann cyclization/decarboxylation sequence
to give a process suitable for the production of kilogram quantities of API.
properties of the reaction mixture, but this did not improve the
yield or the diastereomeric ratio.
INTRODUCTION
■
Alzheimer’s disease is the most common neurodegenerative
disease, currently affecting about 4 million people in the United
States, and as the population ages in the coming decades, this
number is expected to increase substantially. Currently there is
no effective treatment for either preventing or slowing the
progression of Alzheimer’s disease, which is characterized by
cognitive decline, memory loss, and dementia. The develop-
ment of Alzheimer’s disease is associated with the formation of
β-amyloid protein plaques in the brain. The enzyme β-secretase
(BACE) is involved in the formation of the β-amyloid
precursor protein, and compounds that inhibit BACE may be
of use in preventing the formation of β-amyloid protein plaques
implicated in the development of Alzheimer’s disease.1
Spiropiperidines have been developed as targets for the
treatment of Alzheimer’s disease and a variety of other CNS
disorders.2 As part of an ongoing program to develop BACE
inhibitors for the potential treatment of Alzheimer’s and other
neurodegenerative diseases, we needed substantial quantities of
the target API. This manuscript describes the development of a
scalable process for the synthesis of the key spiropiperidine
intermediate 1 and its conversion to the API.3
The correct C-4 stereochemistry was established by a Jocic
reaction of 3 with azide and DBU to yield 4. The reaction
proceeded with inversion at C-4, as demonstrated by single
crystal X-ray determination of the amine 5 resulting from zinc
reduction of 4.4 Acylation with monoethyl malonate followed
by a Dieckmann cyclization yielded the spiro compound 6,
which formed the keto lactam 7 after a facile decarboxylation.
Conversion to the unsaturated lactam 9 was done using NaBH4
reduction to yield 8 as a mixture of diastereomers, followed by
mesylation and elimination with DBU. N-Arylation of the
lactam was accomplished by reaction with 3-fluoroiodobenzene
with CuI and Cs2CO3 in DMEDA/dioxane at 100 °C, yielding
10. Finally, the CBZ protecting group was removed with HCl
and methanol to yield 1. Reductive alkylation of 1 with the
aldehyde 116 yielded the API free base, which was purified by
chromatography and then converted to the HCl salt.
While the synthesis shown in Scheme 1 was suitable for
preparation of the relatively small amounts of API needed for
early toxicology studies, further scale-up of this process would
be problematic. The main issues with the synthesis shown in
Scheme 1 were (1) the diastereoselectivity in the trichlor-
omethyl addition to yield 3 was poor, and this procedure was
nonscalable due to physical problems; (2) an azide was an
intermediate; although the DSC results of intermediate 4 did
not completely preclude its processing (DSC onset 152 °C, 792
J/g), scale-up would be greatly simplified by avoiding the azide
altogether; (3) the work-up of the azide reduction with zinc was
cumbersome; (4) the late stage N-arylation was nonscalable
due to the use of dioxane; (5) chromatography was required for
the purification of intermediates 7 and 10.
RESULTS AND DISCUSSION
■
The key intermediate 1 and the API were originally prepared by
Discovery Chemistry using the route shown in Scheme 1.4 The
synthesis starts from single-enantiomer (S)-benzyl 2-methyl-4-
oxopiperidine-1-carboxylate (2).5 LiHMDS was added to a
mixture of 2 and CHCl3 at < −65 °C to give the desired
diastereomer 3 in about 46% yield after crystallization from
Et2O. The diastereomeric ratio was about 2:1 at best under
these conditions. MgCl2 was added to this reaction to suppress
competing ketone enolization, although its presence did not
alter the diastereomeric ratio. The addition of LiHMDS was
very exothermic, and the reaction temperature needed to be
maintained at < −65 °C to minimize ketone enolization, which
was difficult to accomplish on scale. The reaction had additional
scalability issues due to serious problems with gumming and
balling of the poorly soluble MgCl2 during the reaction and the
formation of emulsions during product isolation. Mg(OTf)2
could be used in place of MgCl2 to improve the physical
To address these issues, we first examined the key
trichloromethyl addition reaction. It was anticipated that use
of a bulkier trichloromethyl-transferring reagent would improve
the diastereoselectivity of the reaction to form 3, and it was
found that in situ generated CCl3-TMS catalyzed by tetra n-
butylammonium acetate gives the desired diastereomer with
Received: May 2, 2013
© XXXX American Chemical Society
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a
Scheme 1. Discovery Synthesis of the API
a
Reagents and conditions: (a) CHCl3, LiHMDS, MgCl2, −65 °C, then crystallization, 46%; (b) NaN3, DBU, 18-crown-6, MeOH, 86%; (c) Zn,
AcOH, 50 °C, 78%; (d) monoethyl malonate, EDC1, Et3N, DCM, then NaOH, EtOH, 86%; (e) dioxane, H2O, 100 °C, chromatography, 88%; (f)
NaBH4, MeOH, 86%; (g) MsCl, Et3N, then DBU, 89%: (h) 3-fluoroiodobenzene, DMEDA, Cs2CO3, CuI, dioxane, 100 °C, chromatography, 84%;
(i) HC1, MeOH, 85%: (j) NaBH(OAc)3, THF, chromatography, then HCl, 92%.
a
Scheme 2. Modified Process
a
Reagents and conditions: (a) CHCl3, LiHMDS, n-Bu4NOAc; (b) TBAF, AcOH, 78%; (c) 3-fluoroaniline, DBU, MeOH; (d) ethylmalonyl chloride,
2,6-lutidine; (e) NaOEt; (f) HC1, H2O, 35% overall from 3; (g) NaBH4 THF, EtOH; (h) MsCl, Et3N, DCM, then DBU; (i) HC1, H2O, 65%
overall from 18.
about 9:1 diastereoselectivity at 0 °C.7 Other potential catalysts
such as sodium formate, cesium acetate, or betaine were
ineffective due to poor solubility. The reaction became sluggish
at lower temperatures, and the diastereomeric ratio did not
substantially improve. The slow non-tetra n-butylammonium
acetate promoted background reaction is somewhat less
selective and gives a diastereomer ratio of about 4:1. The
intermediate TMS ether 12 (Scheme 2) proved to be
remarkably stable. For example, acid promoted desilylation
was quite slow with partial loss of the CBZ group with HCl in
B
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Scheme 3. Mechanism of the Jocic Reaction
a
Scheme 4. Final Modifications
a
Reagents and conditions: (a) 3-fluoroaniline, DBU, ACN, MeOH; (b) ethyl malonyl chloride, 2,6-lutidine, ACN; (c) NaOH, H2O, ACN, 65%
overall from 3; (d) 2-MeTHF, HC1, 95%.
methanol; accordingly, the silyl group was removed with TBAF.
Acetic acid was added to the desilylation reaction to prevent
reversion of the 2,2,2-trichloromethylcarbinol 3 to the ketone 2.
The product was isolated by crystallization from MTBE in 78%
yield on 1 kg scale; this product had about 0.2% of the
undesired diastereomer, and the residual enantiomer was
undetected (<0.1%).
As an alternative to the problematic azide intermediate, we
envisioned an analogous reaction with 3-fluoroaniline (Scheme
3). Prior to this work, there had been only a few isolated
reports of anilines being used in Jocic-type reactions to yield
carboxylic acids, none with any stereochemical issues.8 Despite
the relatively low reactivity of 3-fluoroaniline compared to
azide, reaction of 3 with 3-fluoroaniline and DBU in methanol
successfully gave 13 along with varying amounts of the amide
14 and the methoxy ester 15. Under optimized conditions (3
equiv of 3-fluoroaniline, 8 mL/g methanol) the isolated yield of
13 was about 75%. 13 was not normally isolated, and the
byproducts, mostly 14 and 15, were removed in subsequent
processing. The mechanism for the Jocic reaction is shown in
Scheme 3, and as expected, the reaction with 3-fluoroaniline
proceeded with complete stereospecificity (greater than 20:1
diastereomeric ratio) and complete inversion at the C-4
position.
Among the many bases surveyed, 2,6-lutidine is preferred.
Presumably the reaction proceeds through the sterically non-
demanding and highly reactive ethoxycarbonyl ketene.9 The
Dieckmann cyclization was very facile with a variety of bases
and yielded the ketoester 17 as a poorly characterized mixture
of enol isomers. Deesterification/decarboxylation required
acidic conditions and was also extremely facile; the keto lactam
18 was isolated by crystallization from MTBE−heptane in
about 35% overall yield from 3. The final steps to 1 were
uneventful. NaBH4 reduction gave an inconsequential mixture
of alcohol diastereomers (19, about a 60:40 ratio). The
subsequent mesylation and DBU-mediated elimination to yield
10 were done in one pot without isolation of the intermediate
mesylates. Finally, CBZ removal required drastic conditions (6
M HCl in MeOH at reflux for 18 h) but was otherwise
straightforward. The overall isolated yield of 1 from 18 was
about 65%.
About 250 g of 1 was prepared using the chemistry shown in
Scheme 2 in the first scale-up campaign. Before further scale-up,
additional process development was done. The areas for
improvement encountered during the initial scale-up were
primarily in the conversion of 13 to 18, which had several
complicated aqueous work-ups, lengthy distillations to
exchange solvents, and a relatively low overall yield. For the
final process, further optimization of the Jocic reaction led to
the incorporation of acetonitrile as a co-solvent, which
decreased the amount of 14 and 15 formed. The solvent for
the acylation to form 16 was also changed from DCM to
acetonitrile. It was found that NaOH was an effective base for
the Dieckmann cyclization and at the end of the acylation,
aqueous NaOH was added to the solution containing 16. The
cyclized product was then directly crystallized from acetoni-
The aniline nitrogen in 13 is both sterically hindered and
electronically deactivated, and acylation proved to be
challenging (Scheme 2). The acylation reaction worked well
with ethyl malonyl chloride to yield 16, and with not much else.
For example, acylation of 13 failed with AcCl, acetic anhydride,
CDI, or BOC2O under a variety of conditions. Acylation with
mono ethyl malonate with a variety of activating agents
(including EDCI, EEDQ) also failed to give any product.
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trile−water and isolated as the sodium salt 20 by filtration,
greatly simplifying the processing, improving product yield and
purity, and shortening cycle time. The decarboxylation was
then done in a two-phase mixture of 2-MeTHF and water at a
slightly acidic pH. At the end of the decarboxylation reaction,
the aqueous phase was removed, and the 2-MeTHF was
exchanged to toluene to crystallize 18 in 65% overall yield from
3. The final modifications to the process are shown in Scheme
4. Conversion to the API was done as before by reductive
alkylation with 116 and sodium triacetoxyborohydride. After
purification by chromatography, the free base was converted to
the HCl salt.
1.40 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 155.1, 154.7,
136.6, 128.5, 128.0, 127.9, 127.8, 109.1, 81.1, 67.2, 45.7, 45.5,
34.8, 34.5, 34.3, 31.4, 31.1, 18.5, 17.9.
(5R,7S)-8-Benzyl 3-Ethyl 1-(3-Fluorophenyl)-7-methyl-
2,4-dioxo-1,8-diazaspiro[4.5]decane-3,8-dicarboxylate
Sodium Salt (20). Compound 3 (1.0 kg, 2.72 mol) was stirred
at room temperature in methanol (6 L) and acetonitrile (2 L).
3-Fluoroaniline (0.91 kg, 8.19 mol) was added, and the slurry
was cooled to 0 °C. DBU (1.45 kg, 9.5 mol) was added over 30
min maintaining the temp at 0 °C. The mixture was stirred at
0−20 °C for 6 h and then concentrated to <4 L under full
vacuum. MTBE (10 L) was added, and the mixture was washed
with 1 M HCl (2 × 5 L) and water (5 L). The solution was
concentrated under vacuum. Acetonitrile (10 L) was added, the
solution was concentrated to <4 L under vacuum, and the
residue was redissolved in 10 L of acetonitrile.
CONCLUSION
■
In conclusion, a scalable process for the synthesis of the API
was developed. The final process proceeds in nine linear steps
and is highly telescoped with only four isolated intermediates.
Key features were the development of a novel diastereoselective
trichloromethyl addition and an unprecedented diastereospe-
cific aniline Jocic reaction, which eliminated the need for an
azide intermediate with a troublesome zinc reduction and a
late-stage N-arylation. In addition, streamlined processing was
developed for a Dieckmann cyclization/decarboxylation
sequence. The overall yield of API was about 44% from (S)-
benzyl 2-methyl-4-oxopiperidine-1-carboxylate (2), and approx-
imately 1 kg of API was made using this process.
The solution containing 13 was cooled to 0 °C, and 2,6-
lutidine (0.53 kg, 4.95 mol) was added. Ethyl malonyl chloride
(0.66 kg, 4.38 mol) was added over 1 h maintaining the temp at
0 °C. The mixture was stirred at 0 °C for 1 h. One molar
NaOH (10 L) was added keeping the temp <10 °C, and then
the mixture was stirred for 30 min. The slurry was heated to 40
°C for 2 h and then cooled to 20 °C and stirred for 6 h. The
solids were filtered, washed with acetonitrile (4 L), and dried to
yield 834 g (63%) of 20 as a white solid. Mp: 355−360 °C
1
(dec). H NMR (400.13 MHz, d6-DMSO) δ 7.21−7.38 (m,
6H), 6.95−7.08 (m, 3H), 4.73−5.01 (m, 2H), 4.02 (q, J = 7.0
Hz, 2H), 3.70−3.81 (m, 1H), 3.50−3.60 (m, 1H), 3.15−3.4
(m, 2H), 1.66−2.05 (m, 3H), 1.17 (t, J = 7.0 Hz, 3H), 1.07 (d,
J = 6.3 Hz, 3H). 13C NMR (100.61 MHz, d6-DMSO) δ 194.3,
172.6, 165.9, 163.1, 160.6, 154.0, 140.8, 140.7, 136.9, 129.6,
128.3, 127.2, 126.5, 117.5, 117.3, 113.3, 113.1, 85.2, 65.7, 63.2,
56.9, 45.4, 36.9, 36.3, 31.7, 20.2, 14.8. HRMS (GC-ESI) calcd
for C26H28FN2O6 [(MH + H)+] m/z 483.1931, found
483.1918.
EXPERIMENTAL SECTION
■
( 2 S , 4 S ) - B e n z y l 4 - H y d r o x y - 2 - m e t h y l - 4 -
(trichloromethyl)piperidine-1-carboxylate (3).7 Chloro-
form (810 mL, 10.1 mol) and chlorotrimethylsilane (990 mL,
7.8 mol) were dissolved in THF (3.75 L) and cooled to about
−65 °C internal. LiHMDS (1 M in THF, 7.4 L, 7.4 mol) was
added over 20 min at −60 to −70 °C. The mixture was stirred
at −60 to −70 °C for 20 min and then warmed to about −20
°C over 3 h. (S)-Benzyl 2-methyl-4-oxopiperidine-1-carboxylate
(2, 1.00 kg, 4.04 mol) in DMF (3.16 L) was added over about
30 min, and then tetra n-butylammonium acetate (110 g, 0.69
mol) in DMF (810 mL) was added. The mixture was stirred at
0 °C until the reaction was complete and then warmed to room
temperature. Water (2.8 L) and MTBE (2.8 L) were added.
The organic phase was washed with water (2.8 L), 1 M HCl
(2.8 L), and water (2 × 2.8 L). The organic solution was
distilled under full vacuum (40 °C jacket) to 4 L. 2-MeTHF
(12.2 L) was added, and the mixture was distilled under full
vacuum to about 4 L. Acetic acid (240 mL, 4 mol) and tetra n-
butylammonium fluoride solution in THF (1 M, 4.04 L, 4.04
mol) were added, and the mixture was stirred for 30 min.
K2CO3 (650 g) in water (4 L) was added, and the mixture was
stirred for 30 min. The phases were separated, and the organic
phase was washed with water (3 × 4 L). The organic solution
was distilled under full vacuum to 4 L. DCM (8 L) was added,
and the solution was filtered through 1 kg of Florisil. The
filtrate was distilled under vacuum to 4 L, then MTBE (5 L)
was added, and the distillation was continued under
atmospheric pressure, with MTBE added to maintain a volume
of 7 L, until the head temp was greater than 54 °C. The slurry
was cooled to 0 °C for 12 h and then filtered. Yield: 1164 g
(5R,7S)-Benzyl 1-(3-Fluorophenyl)-7-methyl-2,4-
dioxo-1,8-diazaspiro[4.5]decane-8-carboxylate (18).4
Compound 20 (830 g, 1.64 mol) was stirred in 2-MeTHF
(4.2 L). One molar HCl (2.4 L) was added, and the mixture
was heated to reflux for 1 h. The mixture was cooled to 20−25
°C, and the aqueous phase was removed. The organic phase
was washed with 10% (w/v) aqueous NaCl solution (4.2 L).
Toluene (6 L) was added to the organic solution, and the
mixture was distilled under full vacuum to 6 L, and then cooled
to 0−10 °C. The solids were filtered and dried to yield 646 g
1
(95%) of 7. Mp: 143.4−144.6 °C. H NMR (400.13 MHz,
CDCl3) δ 7.4−7.49 (m, 1H), 7.27−7.39 (m, 5H), 7.13−7.22
(m, 1H), 6.86−6.98 (m, 2H), 4.98−5.12 (m, 2H), 4.27−4.52
(m, 1H), 3.96−4.15 (m, 1H) 3.46−3.6 (m, 1H), 3.39 (d, J =
22.1 Hz, 1H), 3.22 (d, J = 22.1 Hz, 1H), 1.65−2.06 (m, 4H),
1.27 (d, J = 7 Hz, 3H). 13C NMR (100.61 MHz, CDCl3) δ
207.8, 167.8, 164.0, 161.5, 154.3, 136.3, 135.0, 130.7, 128.3,
127.7, 126.2, 126.1, 118.0, 117.7, 116.5, 116.3, 68.8, 67.1, 45.6,
39.9, 35.5, 35.2, 31.5.
(5R,7S)-1-(3-Fluorophenyl)-7-methyl-1,8-diazaspiro-
[4.5]dec-3-en-2-one Hydrochloride (1).3 Compound 18
(500 g, 1.22 mol) was stirred in 2-MeTHF (4 L) and ethanol
(4 L). NaBH4 pellets (95 g, 2.5 mol) were added in portions
over 3 h, and the mixture was stirred for about 4 h. Acetone
(500 mL) was added, and the solution was concentrated under
vacuum to <4 L. Toluene (5 L) was added, and the mixture was
washed with 1 M HCl (4 L) and 5% (w/v) aqueous NaCl
solution (2.5 L) and then distilled under vacuum to <3 L. The
1
(78.9%) of 3 as a white solid. Mp: 146.8−147.9 °C. H NMR
(399.7 MHz, CDCl3) δ 7.30−7.42 (m, 5H), 5.16 (s, 2H),
4.55−4.75 (m, 1H), 4.08−4.28 (m, 1H), 3.21−3.38 (m, 1H),
2.40 (s, 1H), 2.30−2.38 (m, 1H), 1.87−2.24 (m, 3H), 1.36−
D
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residue was dissolved in DCM (9.5 L) to yield a solution
containing 19.
mixture was stirred for 1 h. The solid was filtered and washed
with diethyl ether (1.0 L), then dried using a nitrogen press to
provide the product as an off-white amorphous solid. Yield: 108
g, 92%. Mp: 197.5−199 °C (dec). LC−MS m/z 447.2 (M +
Triethylamine (220 g, 2.17 mol) was added, and the solution
was cooled to 10 °C. Methanesulfonyl chloride (250 g, 2.17
mol) was added keeping the temp about 10 °C. The solution
was stirred for 15 min, then DBU (680 g, 4.47 mol) was added,
and the mixture was stirred for 30 min. The solution was
washed with 1 M HCl (8 L) and 5% (w/v) aqueous NaCl
solution (4 L).
1
H)+. H NMR (400 MHz, d6-DMSO), roughly 60:40 mixture
of rotamers: δ 11.46 and 10.35 (2 br s, total 1H),10.56 (br s,
1H), 7.88 (d, J = 6.2 Hz, 0.6H), [7.01−7.16, 7.19−7.26, 7.28−
7.38 and 7.44−7.57 (4 m, total 8H)], 6.99 (d, J = 8.4 Hz,
0.4H), 6.36 (d, J = 6.2 Hz, 0.6H), 6.17−6.23 (overlapping d, J =
5.9 Hz, at 6.22 and ddd, J = 10.2, 1.7, 0.8 Hz, at 6.19; total
1.4H), 4.10−4.25 (m, 2H), [2.72−2.83 (br m), 3.09−3.19 (br
d, J = 12 Hz), 3.25−3.33 (br d, J = 12 Hz), 3.37−3.52 (br m,
presumed; obscured by water peak) and 3.67−3.77 (br s), total
3H], 2.13 (s, 1.2H), 2.12 (s, 1.8H), [1.82−1.97 (br m) and
2.12−2.48 (m), total 4H], 1.43−1.50 (2 overlapping d, J = 6
Hz, 3H). 13C NMR (100.61 MHz, d6-DMSO) δ 170.5, 169.8,
163.8, 163.6, 161.4, 161.2, 155.5, 153.8, 153.7, 152.8, 140.5,
140.4, 139.7, 139.6, 139.6, 137.5, 133.0, 132.9, 132.4, 131.9,
131.3, 131.2, 127.6, 127.2, 127.2, 127.0, 125.8, 124.9, 120.7,
118.6, 118.4, 118.4, 118.2, 118.0, 117.2, 117.2, 116.1, 116.0,
115.9, 115.8, 105.7, 105.7, 65.1, 64.2, 53.7, 53.1, 52.6, 46.0,
43.5, 38.0, 36.6, 29.5, 29.3, 17.8, 14.2, 11.5, 11.4.
The DCM solution containing 10 was concentrated under
full vacuum, and methanol (6 L) was added. The solution was
concentrated under vacuum to <3 L, water (1.6 L) and
concentrated hydrochloric acid (1.78 kg) were added, and the
solution was heated to reflux for 18 h. The solution was cooled
and extracted with DCM (3 × 2.5 L). NaOH (50%, 2.07 kg)
was added to the aqueous phase. The mixture was extracted
with DCM (2 × 2.5 L). The DCM solution was concentrated
under vacuum, and ethyl acetate (6 L) was added. A solution of
HCl (2.17 mol) in ethyl acetate (2 L) was added, and the
mixture was granulated for 2 h. The solids were filtered and
dried to give 257 g (71%) of 1 as a white solid. Mp: 298−300
1
°C (dec). LC−MS m/z 261.2 (M + H)+. H NMR (400.13
MHz, d6-DMSO) δ 9.0−9.45 (br m, 2H), 7.5−7.58 (m, 1H),
7.46 (d, J = 5.9 Hz, 1H), 7.30−7.37 (m, 2H), 7.2−7.23 (m,
1H), 6.26 (d, J = 5.9 Hz, 1H), 3.26−3.27 (m, 1H), 2.97−3.07
(m, 1H), 2.53−2.65 (m, 1H), 1.96−2.27 (m, 4H), 1.25 (d, J =
6.5 Hz, 3H). 13C NMR (100.61 MHz, d6-DMSO) δ 170.4,
164.0, 161.5, 155.3, 139.6, 131.4, 127.7, 125.0, 118.7, 118.5,
116.3, 116.1, 64.8, 47.7, 38.9, 36.8, 29.2, 18.4.
ASSOCIATED CONTENT
■
S
* Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
(5R,7S)-1-(3-Fluorophenyl)-7-methyl-1,8-diazaspiro-
[4.5]dec-3-en-2-one, Hydrochloride Salt (API).3 Com-
pound 1 (100 g, 0.33 mol) and 4-hydroxy-3-(5-methyl-1H-
pyrazol-1-yl)benzaldehyde (11, 82 g, 0.4 mol) were stirred in
THF (2 L). Triethylamine (69 mL, 0.5 mol) was added, and
the slurry was stirred at room temperature for 30 min. Sodium
triacetoxyborohydride (110 g, 0.52 mol) was added, and the
mixture was stirred until the reaction was complete. Water (200
mL) and 2-MeTHF (1 L) were added, and the pH was adjusted
to about 8 with aqueous NaOH solution. The phases were
separated, and the aqueous phase was extracted with 2-MeTHF
(1 L). The organic solutions were combined and washed with
5% (w/v) aqueous NaCl solution (1 L). The solution was
clarified by filtration through Florisil. The Florisil was rinsed
with 2-MeTHF (2 L), then the combined filtrates and washings
were concentrated under full vacuum, and ethyl acetate was
added. The ethyl acetate was removed under vacuum, and the
crude product was purified by chromatography on silica eluting
with ethyl acetate and ethyl acetate/THF mixtures. The
product-containing fractions were concentrated to yield the
API as a light yellow gum (150 g, 100%). 1H NMR (400 MHz,
CDCl3) δ 9.42 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.39−7.45 (m,
2H), 7.11−7.17 (m, 2H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.01
(d, J = 8.4 Hz, 1H), 6.94 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 6.88
(ddd, J = 9.4, 2, 2 Hz, 1H), 6.25−6.27 (m, 1H), 6.24 (d, J = 6.0
Hz, 1H), 3.51 (dd J = 13.5 Hz, 2H), 2.98−3.07 (m, 1H), 2.66
(ddd, J = 12.5, 10.0, 3.0 Hz, 1H), 2.43 (ddd, J = 12.5, 5.3, 4.4
Hz, 1H), 2.35 (s, 3H), 2.11 (dd, J = 13.3, 5.1 Hz, 1H), 1.97
(ddd, J = 13.0, 10.0, 4.2 Hz, 1H), 1.68−1.76 (m, 1H), 1.55−
1.63 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H).
Corresponding Author
kevin.e.henegar@pfizer.com
Notes
The authors declare no competing financial interest.
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