Enabling Synthesis of Triple Reuptake Inhibitor (+)-BMS-820836, a Potential Therapeutic Agent for the Treatment of Depression

Article abstract of DOI:10.1021/acs.oprd.5b00261

Herein, we describe the enabling synthesis of (+)-BMS-820836, a 4,7-disubstituted tetrahydroisoquinoline which was developed as a treatment for a range of neurological diseases, including depression and neurophatic pain. In order to advance the drug candi

Full text of DOI:10.1021/acs.oprd.5b00261

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Full Paper
Enabling Synthesis of Triple Reuptake Inhibitor (+)-BMS-820836,
a Potential Therapeutic Agent for the Treatment of Depression.
Paul C. Lobben, Rasidul Amin, Bang-Chi Chen, Wenge Cui, Min Hu,
Matthew Isherwood, Shuang Liu, Kassoum Nacro, Brandon Miles, Bingidimi
Itute Mobele, Richard E. Olson, Bei Wang, Yuh-Lin Yang, and Rulin Zhao
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00261 • Publication Date (Web): 22 Dec 2015
Downloaded from http://pubs.acs.org on December 22, 2015
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Enabling Synthesis of Triple Reuptake Inhibitor (+)-BMS-820836, a potential
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Therapeutic Agent for the Treatment of Depression.
Paul C. Lobben*,†, Rasidul Amin⊥, Bang-Chi Chen§, Wenge Cui//, Min Hu//, Matthew
Isherwood//, Shuang Liu//, Kassoum Nacro//, Brandon Miles⊥, Bingidimi Mobele⊥, Richard
E. Olson‡, Bei Wang§, Yuh-Lin Yang//, and Rulin Zhao§
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† Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903, USA
‡ Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford,
CT 06492, USA
§ Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA
∥
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, USA
⊥
Chemical Development Department Albany Molecular Research, Inc. 21 Corporate Circle Albany, NY 12203, USA
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TABLE OF CONTENTS GRAPHIC
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ABSTRACT
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Herein, we describe the enabling synthesis of (+)-BMS-820836, a 4,7-disubstitued
tetrahydroisoquinoline which was developed as a treatment for a range of neurological diseases,
including depression and neurophatic pain. In order to advance the drug candidate into the Phase 1
clinical trials, an efficient and scalable synthesis was required. Three areas of improvement included
the development of a regioselective Friedel-Crafts cyclization, a classical resolution for the purification
of the desired enantiomer, and a robust Suzuki-Miyaura coupling. These improvements ultimately
resulted in the isolation of (+)-BMS-820836 as a free flowing white solid in 99 area% purity and 3%
overall yield after 14 steps.
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Key words: Suzuki-Miyaura coupling, Friedel-Crafts cyclization
INTRODUCTION
Major depressive disorders are a condition of high prevalence and very high burden on the global
health care system and is the fourth leading cause of disease burden according to the World Health
Organization.1 The prevalence of the disease in the United States is estimated at over 6% in a twelve
month period and 16% over a lifetime.2 The symptoms associated with major depression fall into two
categories, that of a depressed mood and that of a loss of pleasure (anhedonia).3 Major depression is
typically associated with a hetereogenous dysregulation of the monoaminergic systems. Selective
serotonin reuptake inhibitors (SSRIs) and dual serotonin/norepinephrine reuptake inhibitors (SNRIs),
are proven therapies for depression. The response rate of current antidepressants is reported to be on
the order of 65%, while remission from the disorder is only about 30%.4 The onset of action for current
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therapeutic agents is not rapid, and may take up to four weeks to evoke a response. A compound that
shortens the response rate, improves remission, and diminishes the onset of action would represent a
considerable improvement over current therapies. With these goals in mind, Bristol-Myers Squibb, in
collaboration with Albany Molecular Research, Inc. (AMRI) developed triple reuptake inhibitors (TRIs)
as potential antidepressants.5
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The aim of the triple reuptake inhibitor (TRI) program was to add dopamine inhibition to the already
well established mechanisms of SERT and NET inhibition. Dopamine is known to be involved in
centrally mediated reward responses and the inhibition of dopamine reuptake transporters (DAT)
elevates synaptic dopamine levels.5a,5b As part of these efforts, (+)-BMS-820836 was identified as a
potent TRI. Further clinical development of (+)-BMS-820836 required an efficient and scalable
synthesis of this novel tetrahydroisoquinoline (THIQ) from readily available starting materials shown in
Figure 1.
Figure 1. Retrosynthesis for the preparation of BMS-820836
The THIQ motif can be found in natural products and is of general synthetic interest.6 The first
synthesis of (+)-BMS-820836 developed by the Discovery Chemistry group used m-bromobenzaldehyde
(1), methylamine, 2-bromo-2’-acetonaphthone (3) and 3-chloro-6-aminopyridazine as starting
materials (Scheme 1). The synthesis was expedient, affording (+)-BMS-820836 in seven steps albeit
requiring two chromatography operations in order to isolate the final product with the necessary
purity. Steps 1-3 were nearly quantitative in yield, yet each intermediate was isolated as an oil and
with only moderate purity. The acid-mediated Friedel-Crafts cyclization of 5 gave an unselective 1:1
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ratio of the undesired C-5 and desired C-7 THIQ 6.7 These isomers were separated with difficulty by
silica gel chromatography. Finally, following Suzuki-Miyaura coupling the desired (+)-BMS-820836 was
obtained by preparative chiral HPLC on a CHIRACEL OD column in 28% yield over the two steps.
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The synthesis represented in Scheme 1 was straightforward and was utilized for the preparation of (+)-
BMS-820836 on a multi-gram scale. However, there were several challenges to this route. First,
intermediates 2, 4, and 5 were only able to be isolated as oils. Second, the poor regioselectivity
observed in the Friedel-Crafts cyclization required chromatographic purification of the desired C-7
THIQ 6. Ultimately chiral chromatography was required to isolate (+)-BMS-820836 as a single
enantiomer. We had concerns regarding the modest yield and reproducibility of the Suzuki-Miyaura
reaction. Finally we expected that a metal mediation strategy would be required to minimize residual
palladium in the drug substance used for Phase 1 clinical trials.8
Scheme 1. Discovery Synthesis of BMS-820836
RESULTS AND DISCUSSION
Herein, we report on the development of a route to (+)-BMS-820836 that provided fit-for-purpose
solutions to the challenges outlined above.9 Our goal was to advance the clinical program quickly. To
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accomplish this we desired a more efficient synthesis that avoided chromatography and provided
greater throughput. An expedient fit-for-purpose synthesis would support early toxicological studies
and rapid initiation of Phase 1 clinical studies. We anticipated that improving the regioselectivity of the
Friedel-Crafts alkylation and defining conditions to isolate and purify the desired C-7 regioisomer and
enantiomer without using chromatography would be key objectives for meeting the aggressive
timelines of the Phase I program.
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The synthesis of the THIQ core started with the reductive amination of m-anisaldehyde and methyl
amine (Scheme 2). NaBH4, 0.6 equivalents (optimized) was added, in portions to maintain the internal
temperature < 10 °C, to a cold, clear solution of m-anisaldehyde and methyl amine in methanol. The
resulting secondary amine 9 was isolated as an oil, in good yield and with acceptable purity for
downstream processing.10 Alkylation of crude 9 with bromoketone 3 was accomplished with
triethylamine in DCM at <5 °C (Table 1, entry 1). Other solvents provided lower yields and lower purity.
Due to its limited stability, compound 10 was immediately reduced with NaBH4 in MeOH at low
temperature. The resulting alcohol 11 was extracted into DCM. After an aqueous work-up the desired
product was isolated as an oil in nearly quantitative yield and adequate purity for use in the Friedel-
Crafts alkylation reaction. The use of methoxy-derivative 10 improved the regioselectivity of the
Friedel-Crafts acylation 2.4 fold over the para-bromo derivative under standard conditions, favoring
the desired C-7 isomer.11 The best conditions for cyclization required 10 equivalents of CH3SO3H in
CH2Cl2 at -10 oC.12 After an aqueous work-up, 12, as a mixture of 2.4:1 regioisomers, was isolated as an
oil in 71% yield.
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Table 1. Solvent selection for alkylation of 9 with bromo-2-acetonaphthanone (3).
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Entry
Solvent
Crude
Yield
97%
83%
73%
84%
72%
85%
52%
47%
Purity
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DCM
EtOAc
IPAC
81%
86%
77%
80%
58%
70%
73%
52%
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MTBE
MeOH
EtOH
THF
ACN
Our strategy was to isolate the desired C-7 isomer 12 from the crude mixture of regioisomers via salt
formation and thereby circumvent the need for chromatography. To this end, treatment of the crude
mixture with one equivalent of oxalic acid in ethanol resulted in the formation of a crystalline oxalate
salt. Analysis of the product revealed a significant enrichment in the desired C-7 isomer 12 with a
favorable 90:10 ratio. A single reslurry in hot ethanol improved the ratio to 98:2. Subsequent salt break
with aqueous NaOH afforded racemic 12 with 97 area% purity and in 50% yield from intermediate 10.
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Table 2. DTTA resolution of racemic 12 in acetone
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Entry Solvent
DTTA Equiv. Yield
e.e.
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EtOH
EtOH
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28%
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90%
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EtOH
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After completing the chromatography-free synthesis of the racemic C-7 THIQ 12 core we focused our
attention on the isolation of the desired enantiomer. In order to avoid the chiral chromatography, we
explored the feasibility of a classical resolution of the enantiomers of 12. Gratifyingly, from a focused
screen of three non-racemic acids, dibenzoyl-D-tartaric acid, (1S)-(+)-10-camphor sulfonic acid, and di-
p-toluoyl-D-tartaric acid (D-DTTA), the latter acid provided a suitable solid product (Table 2).13, 6e
Careful selection of the solvent, concentration, and acid stoichiometery led to the identification of
conditions under which the desired C-7 enantiomer 13 could be isolated in an acceptable yields (26-
35%) and with 94-98% ee. The optimized procedure required two sequential resolutions using D-DTTA
in acetone. On a kilogram scale, a slow addition of an acetone solution of D-DTTA (0.75 equiv) over no
less than four hours at 55 °C afforded 13 in 90% ee and 40% yield (Table 3). A second iteration with D-
DTTA (0.90 equiv) yielded 13 in ≥99% e.e. and 94% yield. Efforts to racemize and recycle the undesired
enantiomer proved unsuccessful.14
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Table 3. Resolution of racemic 12 using DTTA in acetone
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first iteration
second iteration
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Entry DTTA
yield e.e. DTTA yield e.e.
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0.75
0.90
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mol%
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35% 94% mol% 71% 99%
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26% 98% mol% 90% 99%
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26% 96% mol% 88% 99%
0.90
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40% 92% mol% 94% 99%
Demethylation of 13 under standard conditions was accomplished with aqueous HBr in acetic acid at
105 °C. No erosion of e.e. was observed under the reaction conditions. The hydrobromide salt 14 was
crystallized directly from the reaction mixture following the slow addition of water and seeds. After
cooling to room temperature, 14 was isolated by filtration in 96% yield and >97 area% purity as an off-
white solid. The ability to isolate and use the hydrobromide salt directly avoided a complicated quench
and tedious isolation of the free base. It also provided a stable, crystalline intermediate that could be
fully characterized and stored under ambient conditions.
In order to install a synthetic handle for the Suzuki-Miyaura cross-coupling reaction, the phenol
intermediate 14 was first converted into the aryl triflate 15. The use of Et3N as the base and the careful
control of the reaction temperature at -55 °C were identified as the two key parameters for optimal
performance.15 Following an extractive work-up, the crude triflate 15 was obtained in nearly
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quantitative yield and was used directly in the subsequent Miyaura borylation. Pd(dppf)Cl2 as the
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catalyst and potassium acetate as the base provided the pinacol boronate derivative 16.16
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Improving the robustness of the Suzuki-Miyaura reaction was an objective. In the first synthesis of (+)-
BMS-820836 the cross-coupling reaction was carried out as the last step of the synthesis by using 6-
chloropyridazin-3-amine as the electrophilic partner (Scheme 1). This approach required a relatively
high catalyst loading of 8mol% and resulted in an unpredictable conversion and afforded a variable
yield. In addition, this approach placed importance on impurity control, including residual metals, in
the final isolation and was thus deemed undesirable.17 The extremely low solubility of the API in
common organic solvents was another factor that was considered when designing an alternative end-
game. The use of bis-Boc protected analog of pyridazine 1718 greatly increased the solubility of
penultimate intermediate 18 and provided an easy handle to prepare the API by a simple acid-
catalyzed deprotection. These synthetic modifications resulted in predictable performance and
consistent quality with minimal batch-to-batch variability.
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The Suzuki-Miyaura cross-coupling between 16 and 17 worked well under optimized conditions. Fully
sparging the reaction mixture and reagents streams with nitrogen reduced the quantity of catalyst
needed by 60% and afforded a more predictable impurity profile. Upon reaction completion the cross-
coupling product 18 was produced as a brown solid in 70% yield but was contaminated with 1%
palladium and 0.1% iron.
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Scheme 2. Enabling Synthesis of (+)-BMS-820836
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In order to minimize metal contamination in the isolated API, the aqueous work-up and the use of solid
supports were evaluated. Optimization of the aqueous work-up reduced the palladium five-fold to
0.2% and the iron three fold to 500 ppm. A screen of commercially available solid supports and
absorbents such as charcoal, silica and commercial resins, identified Si-Thiol available from SiliCycle®.
Accordingly, two successive treatments with Si-thiol afforded 18 as a white to off-white solid with 70%
recovery and with 3 ppm residual palladium.
Deprotection of both Boc groups of penultimate 18 was accomplished using anhydrous HCl in
isopropanol. Control of the batch temperature, the equivalents of HCl, and the reaction time
minimized the most significant process-related impurity resulting from trans-carbamoylation of the
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tert-butyl group with the isopropanol. Subsequent salt break with aqueous NaHCO3 afforded (+)-BMS-
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820836 as a white solid in 93% yield and >99 area% purity.
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CONCLUSION
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An enabling synthesis of (+)-BMS-820836 that improved the efficiency and throughput over the original
discovery route has been developed. The API was isolated as a free flowing white solid in >99 area%
purity and 3% overall yield and fourteen steps; seven steps longer than the discovery route. The
resulting high quality API supported the aggressive timelines of both the enabling toxicology studies
and the clinical development plan. The highlights of the synthesis include the improved regioselectivity
of the Friedel-Crafts acylation using the methoxy substituent to afford a 2.4 fold improvement in the
regioselectivity. Subsequently, two additional steps were necessary to generate the tosylate from the
methoxy substituent in advance of the Suzuki-Miyaura coupling. The use of oxalic acid and di-p-toluoyl-
D-tartaric acid added four steps to the synthesis, including two requisite salt breaks. This improvement
facilitated the isolation of the non-racemic tetrahydroisoquinoline core as a crystalline salt and avoided
purification by column chromatography. The optimized Suzuki-Miyaura coupling provided the
protected drug substance in a consistent yield of 45-50%, with purity of 99 area% and less than 5 ppm
palladium. An added metal remediation step using Si-Thiol achieved <5 ppm palladium in the final API.
Deprotection and subsequent salt break afforded the free-base of (+)-BMS-820836 as a white solid in
>99 area% purity.
EXPERIMENTAL SECTION
Unless otherwise noted, reagents and solvents were used as received from commercial suppliers.
Proton nuclear magnetic resonance spectra were obtained on a Bruker AV-300 spectrometer at 300
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MHz or a Bruker AVANCE 500 spectrometer at 500 MHz, using tetramethylsilane as an internal
standard for proton spectra. The mass spectra were obtained on a Finnigan LCQ-DUO spectrometer
using electrospray ionization in the positive mode. Reactions were monitored by reverse-phase HPLC
or thin layer chromatography (TLC). Unless otherwise noted, yields are uncorrected for purity or
potency.
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Preparation of 9. To a solution of m-anisaldehyde (2.6 kg, 19 mol) in MeOH (18.2 L) that was cooled to
5–10 °C was added a solution of 40 wt% methylamine in water (1.65 L, 19.1 mol) at a rate to maintain
an internal temperature of 5–10 °C. After the reaction mixture was stirred for 30 minutes, NaBH4 (450
g, 12 mol) was added in five portions to maintain a batch temperature of <10 °C. After the addition was
complete, the reaction mixture was warmed to 20 °C and was stirred until the reaction was deemed
complete, as determined by TLC. Water (5.2 L) was added to the reaction mixture a rate to maintain an
internal temperature of <25 °C. After agitating the reaction mixture for no less than three hours, the
volatile components were distilled under reduced pressure at 30–40 °C until a volume of
approximately 7 L. Isopropyl acetate (IPAc, 26 L) and a 20 wt% brine solution (26 L) were successively
added and the biphasic mixture was stirred for no less than 15 minutes. The layers were separated and
the aqueous layer was extracted once with IPAc (26 L). The combined organic layers were concentrated
by rotary evaporation to provide 8 (2.9 kg, 19 mol, >95% yield) as an oil in 80 area% purity as
determined by HPLC. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H), 6.88–6.90 (m, 2H), 6.79 (dd, J
= 8.5, 2.5 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 2H), 2.48 (s, 3H), 1.41 (br s, 1H).
Preparation of 10. A solution of the 3 (4.4 kg, 18 mol) in DCM (19.8 L) was cooled to 0 °C prior to the
drop-wise addition of 8 (2.8 kg, 19 mol) as a solution in DCM (12.6 L) at a rate to maintain an internal
temperature of <5 °C. The reaction mixture was stirred for 30 min. prior to the addition of Et3N (2.5 L,
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18 mol.) at a rate to maintain an internal temperature of <10 °C. The reaction mixture was then
warmed to 25 °C and was stirred until the reaction was deemed complete, as determined by HPLC
analysis. The reaction mixture was washed with water (19.8 L) and the phases were separated and the
organic layer was concentrated under reduced pressure to afforded 10 (6.2 kg, 19 mol, >95% yield) as a
dark oil. 1H NMR (500 MHz, d-DMSO) δ 8.64 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.97-8.03 (m, 3H), 7.65 (dt,
J = 15.0, 6.9 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 6.88–6.93 (m, 2H), 6.82 (dd, J = 8.1, 2.4 Hz, 1H), 3.99 (s,
2H), 3.68 (s, 3H), 3.66 (s, 2H), 2.27 (s, 3H).
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Preparation of 11. A solution of 10 (5.0 kg, 16 mol) in MeOH (34.8 L) was cooled to –5 °C. NaBH4 (0.54
kg, 14 mol) was added in portions over 4 h in order to maintain an internal temperature of <0 °C. The
reaction mixture was warmed to 15 °C and was stirred for 30 min until the reaction was complete, as
determined by TLC. Water (15 L) was added and the resulting mixture was stirred for 3 h. The volatile
components were removed under reduced pressure to a volume of approximately 20 L. The mixture
was partitioned with DCM (25 L) and the phases were separated. The isolated organic layer was
concentrated to a constant weight under reduced pressure to afford 11 (5.0 kg, 16 mol, >95% yield) as
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a dark oil in with 61 area% purity as determined by HPLC. H NMR (300 MHz, CDCl3) δ 7.76–7.93 (m,
4H), 7.41–7.53 (m, 3H), 7.23–7.31 (m, 1H), 6.86–6.97 (m, 2H), 6.85 (dd, J = 6.0, 2.5 Hz, 1H), 4.96 (dd, J =
10.0, 4.0 Hz, 1H), 3.85 (s, 3H), 3.78 (d, J = 13.1 Hz, 1H), 3.58 (d, J = 13.1 Hz, 1H), 2.69-2.73 (m, 2H), 2.39
(s, 3H).
Preparation of 12. A solution of 11 (625 g, 1.94 mol) in DCM (6.3 L) was cooled to –10 °C prior to the
slow dropwise addition of CH3SO3H (1.26 L, 19.4 mol) at a rate in order to maintain an internal
temperature of <5 °C. Caution: the addition is strongly exothermic. The reaction mixture was warmed
to room temperature and was stirred for 14 h until the reaction was complete, as determined by TLC.
The reaction mixture was cooled to –10 °C and a solution of 50 wt% NaOH (1.5 L) was added followed
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by water (750 mL). The layers were separated and the isolated organic layer was concentrated under
reduced pressure to give 12 (0.55kg, 93% yield) as a brown oil.
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To a solution of 12, as a 2.4:1 mixture of regioisomers [547 g, 1.80 mol) in absolute EtOH (2 L) at room
temperature was slowly added a solution of oxalic acid (162 g, 1.80 mol) in absolute EtOH (0.6 L) in a
single portion. Caution: the addition is exothermic. The reaction mixture was held with agitation until a
precipitate formed. After two additional hours the slurry was filtered to provide 12 as a light yellow
solid and a 9:1 mixture of regioisomers. The resulting filter cake was combined with absolute EtOH (6.5
L) and the resulting slurry was heated at 75 °C for 3 h. The slurry was cooled to 25 °C and filtered. The
dried solids were partitioned between saturated NaHCO3 (3 L) and EtOAc (3.5 L). The organic layer was
isolated and dried over MgSO4. After filtration, the organic layer was concentrated under reduced
pressure to afford 12 (355 g, 1.18mol and 91% yield, corrected) as a white solid and 98 area% purity
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and a 96:4 mixture of isomers. H NMR (300 MHz, CDCl3) δ 7.72–7.82 (m, 3H), 7.68 (s, 1H), 7.39–7.48
(m, 2H), 7.27 (dd, J = 8.4, 1.7 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H), 4.39
(dd, J = 8.4, 5.8 Hz, 1H), 3.78 (s, 3H), 3.77 (d, J = 14.9 Hz, 1H), 3.61 (d, J = 14.9 Hz, 1H), 3.08 (ddd, J =
11.5, 4.3, 1.2 Hz, 1H), 2.64 (dd, J = 11.5, 8.9 Hz, 1H), 2.44 (s, 3H).
Preparation of 13. A solution of racemic 12 (1.2 kg, 4.0 mol) as a 96:4 mixture of regioisomers) in
acetone (48 L) was heated to 55 °C. A portion (7.2 L) of a solution of di-p-toluoyl-D-tartaric acid (1.2 kg,
2.8 mol) in acetone (12 L) was added over 2 h imparted a cloudy reaction mixture. Seed crystals of 13
(0.1 wt%) were then added. The reaction mixture was stirred for an additional 30 min. The remaining
resolving agent (4.8 L) was slowly added over 3 h. The reaction mixture was cooled to –5 to 5 °C over 5
h and was held for 14 h. The slurry was filtered and the filter cake was conditioned for 6 h under a
nitrogen atmosphere. The dried filter cake was partitioned between 2 M aqueous NaOH (3.6 L) and
MTBE (12 L). The biphasic mixture was vigorously stirred for 45 min. The phases were separated and
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the organic layer was concentrated to afford 13 (0.48 kg, 1.6 mol, 80% yield) as an off-white with 82%
e.e.
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The isolated solid obtained underwent a second iteration of the resolution process with only two
minor changes: 1) the stoichiometry of the resolving agent DTTA was increased from 0.80 equiv to 0.85
equiv and 2) the acetone was increased from 40 vol to 50 vol in the initial solution. As a result 13 (0.37
g, 1.2 mol, 97% yield, corrected) was isolated as an off-white and with 99 area% purity and with >99%
e.e. 1H NMR (300 MHz, CDCl3) δ 7.72–7.82 (m, 3H), 7.68 (s, 1H), 7.39–7.49 (m, 2H), 7.24 (dd, J = 8.5, 1.7
Hz, 1H), 6.76 (d, J = 9.4 Hz, 1H), 5.59–6.67 (m, 2H), 4.39 (dd, J = 8.9, 5.9 Hz, 1H), 3.82 (d, J = 15.0 Hz,
1H), 3.76 (s, 3H), 3.67 (d, J = 15.0 Hz), 3.11 (ddd, J = 11.5, 5.7, 1.1 Hz, 1H), 2.66 (dd, J = 11.6, 9.3 Hz, 1H),
2.45 (s, 3H).
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Preparation of 14. A mixture of 13 (1.0 kg, 3.3 mol) in AcOH (2.5 L) was mechanically stirred and was
heated at 55–60 °C until the the reaction mixture was homogeneous. HBr, 48 wt%, in water (5.0 L, 44
mol) was added and the resulting heterogeneous solution was heated to 105 °C to achieve a
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homogeneous solution. After 18 hours, the reaction was deemed complete by H NMR analysis. The
solution was cooled to 95 °C over 15 min. Water (0.9 L) was added over 15 min and seeds of 14 (0.5
wt%) were added. Additional water (3.1 L) was added over 2 h. The resulting slurry was cooled to 25 °C
over 2.5 h and filtered. The filter cake was conditioned under nitrogen overnight. The isolated solids
were combined with water (4.0 L). The resulting slurry was stirred at ambient temperature for 45 min,
was cooled to 5 °C, and was filtered. The isolated solids were conditioned under N2 overnight, and then
were dried in vacuo to a constant weight to afford 14 (1.0 kg, 2.7 mol, 85% yield) as a white solid in >99
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area% purity, as determined by HPLC. H NMR (500 MHz, d-DMSO) δ 10.31 (s, 0.85H), 10.11 (br s,
0.15H), 9.60 (s, 1H), 7.61–7.94 (m, 4H), 7.47–7.59 (m, 2H), 7.30 (d, J = 7.5 Hz, 1H), 6.69 (s, 1H), 6.50–
6.71 (m, 2H), 4.31–4.77 (m, 1H), 4.54 (br s, 2H), 3.84 (br s, 1H), 3.62 (t, J = 11.2 Hz, 1H), 2.98 (s, 3H).
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Preparation of 15. To a solution of 14 (1.0 kg, 2.7 mol) in DCM (12.4 L) at room temperature was slowly
added Et3N (0.90 L, 6.5 mol) (slightly exothermic). After stirring for 20 min, the reaction mixture was
cooled to –55 °C followed by the slow drop-wise addition of Tf2O (0.56 L, 3.3 mol) over 2.5 h. The
internal temperature was maintained below –50 °C. At this point, the reaction was deemed completed,
as determined by HPLC analysis. The reaction mixture was warmed to –10 °C and was quenched with
10% aqueous NaHCO3 (6.2 L). The resulting biphasic mixture was warmed to 20 °C and was stirred for
30 min. The layers were separated, and the organic phase was washed with water (6.2 L) and
concentrated under reduced pressure to provide 15 (1.2 kg, 2.8 mol, >95% yield) as a dark red oil in 74
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area% purity, as determined by HPLC analysis. H NMR (500 MHz, d-DMSO) δ 7.89–7.97 (m, 3H), 7.76
(s, 1H), 7.40–7.49 (m, 2H), 7.28–7.34 (m, 2H), 7.18 (dd, J = 8.6, 2.7 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.43
(t, J = 6.2 Hz, 1H), 3.66–3.74 (dd, J = 20.8, 15.8 Hz, 2H), 2.99 (dd, J = 11.6, 5.6 Hz, 1H), 2.71 (dd, J = 11.5,
5.2 Hz, 1H), 2.35 (s, 3H).
Preparation of 18. To a solution of 15 (1.18 kg, 2.80 mol) and DMSO (16.5 L) was added successively
bis-pinacolato diboron (0.85 kg, 3.3 mol) and KOAc (0.82 kg, 8.4 mol). The heterogeneous mixture was
sparged with nitrogen for 1.5 h. PdCl2(dppf) (60 g, 74 mmol) was added and the reaction mixture was
stirred at 85 °C under nitrogen. After an additional 2.5 h the reaction was complete with <5% of 15, as
determined by HPC analysis. A nitrogen-sparged solution of Cs2CO3 (2.7 kg, 8.4 mol) in water (4.2 L)
was added in one portion. A nitrogen-sparrged slurry of 17 (1.15 kg, 3.49 mol) in DMSO (6.5 L) was
then added in a single portion. Caution: exothermic. A second and final charge of PdCl2(dppf) (60 g, 74
mmol) was added. The reaction mixture was stirred at 85 °C for 12 h. The reaction was complete, as
determined by HPLC analysis Water (5.0 L) was added and after stirring for 1 h, the mixture was filtered
to afford a brown solid which was conditioned under N2 overnight.
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The dried filter cake was dissolved in DCM (18 L) and the organic layer was washed successively with a
10% aqueous LiCl solution (18 L) and a 10% aqueous NH4OH solution (18 L). The DCM layer was
concentrated under reduced pressure. The resulting brown solid was combined with MeOH (6 L); the
resulting slurry was stirred at 55 °C for 1 h, cooled to 25 °C and diluted with EtOAc (12 L). The slurry
was stirred for an additional hour and filtered. The filter cake was conditioned under N2 overnight to
give 18 (0.75 kg, 1.3 mol) as a gray solid. ICP analysis indicated the palladium content was 2300 ppm.
The isolated solid was dissolved in DCM (3.75 L) and was treated with Si-Thiol (1.50 kg, 2 wt% equiv.,
SiliCycle). The reaction mixture was stirred at 30–35 °C for 4.5 h, cooled to room temperature and
filtered. The resin was rinsed with DCM (7.5 L). The combined dark brown organic layers were filtered
through a 1.2-micron filter and concentrated under reduced pressure to afford an off-white solid. ICP
analysis indicated the palladium content was 160 ppm. A second iteration of the metal-remediation
process was performed to also give an off-white solid. ICP analysis indicated the palladium content was
3 ppm. The isolated solid was combined with EtOAc (4.2 L) and the resulting slurry was stirred at
ambient temperature for 1 h and filtered. The filter cake was rinsed with EtOAc (500 mL). The filter
cake was conditioned under N2 for two days to afford 18 (0.72 g, 1.3 mol, 47% yield) as a white solid
with >99 area% purity, as determined by HPLC analysis. 1H NMR (500 MHz, d-DMSO) δ 8.31 (d, J = 9.1
Hz, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.83–7.92 (m, 5H), 7.79 (s, 1H), 7.46–7.51 (m, 2H), 7.39 (dd, J = 8.5, 1.5
Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 4.49 (t, J = 6.3 Hz, 1H), 3.78 (dd, J = 15.4, 21.9 Hz, 2H), 3.02 (dd, J =
11.5, 6.6 Hz, 1H), 2.73 (dd, J = 11.4, 7.1 Hz, 1H), 2.39 (s, 3H), 1.41 (s, 18H).
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Preparation of 17. A mixture of the 6-chloro-pyridazine-3-aminr (0.50 kg, 3.9 mol) and DMAP (3.77 g,
30.9 mmol) in DMF (3.5 L) was heated to 55 °C and was stirred for 20 min to achieve a homogeneous
solution. A solution of Boc2O (1.9 kg, 8.6 mol) in DMF (0.5 L) was charged in a single portion. Caution:
the addition is endothermic. The reaction mixture was stirred at 55 °C for 5 h; at which time the
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reaction was deemed complete, as determined by HPLC analysis. The reaction was cooled to room
temperature. Water (4.4 L) was slowly added; the resulting slurry was stirred for 10 min and then
filtered. Note: Exothermic addition and gas evolution.
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The brown solid was conditioned overnight under nitrogen. The dried solids were combined with 2-
propanol (3.5 L). The mixture was heated at 65 °C to obtain a homogeneous solution. Water (3.5 L) was
added over 30 min and the reaction mixture was cooled to room temperature to afford a slurry. The
solids were isolated and dried to give 17 as a light brown solid (0.81 kg, 2.4 mol, 63% yield) in 99.7
area% purity by HPLC. 1H NMR (300 MHz, d-DMSO) δ 8.00 (dd, J = 9.0, 15.0 Hz, 2H), 1.40 (s, 18H).
Preparation of BMS-820836-2HCl. A mixture of 18 (0.75 kg, 1.3 mol) in isopropyl alcohol (3.75 L) was
stirred at room temperature as 5–6 N HCl in isopropyl alcohol (3.75 L, 18.8 mol) was added over 5 min
(slightly exothermic). The mixture was then heated to 70 °C and held for 18 h, during which time the
mixture became a homogeneous yellow solution, and then a white slurry forms. The reaction was
deemed complete by HPLC analysis. The mixture was cooled to 25 °C and EtOAc (8 L) was added. After
stirring for 1 h, the reaction mixture was filtered to provide BMS-820836-2HCl as a white solid (0.56 kg,
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1.3 mol, >95% yield) with >99 area% purity by HPLC. H NMR (500 MHz, d-DMSO) δ 12.05 (br s, 1H),
8.83 (br s, 2H), 8.38 (d, J = 9.7 Hz, 1H), 7.90–7.98 (m, 5H), 7.76 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 9.7 Hz,
1H), 7.55 (m, 2H), 7.33 (s, 1H), 6.93 (d, J = 5.3 Hz, 1H), 4.88–4.98 (m, 1H), 4.68 (br s, 2H), 3.85–3.93 (m,
1H), 3.70–3.81 (m, 1H), 3.55 (br s, 1H), 2.97 (s, 3H).
Preparation of (+)-BMS-820836. To a solution of BMS-820836-2HCl (0.55 kg, 1.3 mol) in 50% MeOH
(aq) (16.5 L) at room temperature was slowly added a 10% aqueous NaHCO3 (4.4 L) After reaching the
cloud point with approximately 0.4 L added, seed crystals of BMS-820836-03 (10.5 g, 2 wt%) were
added and the thin slurry was stirred for an additional 1 h. During this time the reaction mixture
became very thick. The remaining aqueous NaHCO3 solution (4 L) was added over 40 min and the
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reaction mixture was stirred for 2 h and then filtered. After conditioning on the filter under N2 for 1 h,
the wet filter cake was re-suspended in 20% MeOH(aq) (5.5 L), was stirred for 2 h, and then was
filtered. The filter cake was conditioned under N2 for 48 h and then dried in vacuo at 35 °C for 48 h to
afford BMS-820836 as a white solid (0.45 kg, 1.2 mol, 98% yield) with >99 area% purity as determined
by HPLC. 1H NMR (500 MHz, d-DMSO) δ 7.82–7.94 (m, 3H), 7.74–7.82 (m, 3H), 7.66 (dd, J = 8.1, 1.5 Hz,
1H), 7.44–7.51 (m, 2H), 7.37 (dd, J = 8.4, 1.4 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H),
6.48 (s, 2H), 4.43 (t, J = 6.2 Hz, 1H), 3.72 (dd, J = 22.3, 15.1 Hz, 2H), 2.98 (dd, J = 11.3, 5.5 Hz, 1H), 2.69
(dd, J = 11.4, 7.2 Hz, 1H), 2.36 (s, 3H).
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AUTHOR INFORMATION
Corresponding Author
*E-mail: paul.lobben@bms.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Dr. Frank A. Rinaldi for his assistance with
NMR spectroscopy.
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REFEENCES
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7 (a) Philippe, N.; Denivet, F.; Vasse, J.-L.; Sopkova-de Olivera Santos, J.; Levachera, V.; Dupas, G.
Tetrahedron 2003, 59, 8049–8056. (b) Hart, D. J.; Cain, P. A.; Evans, D. A. J. Am. Chem. Soc. 1978, 100,
1548-1557.
8 Bullock, K.M.; Mitchell, M.B.; Toczko, J.F. Org. Process Res. Dev. 2008, 12, 896-899.
9 With a fit-for-purpose approach, development efforts were focused on solving the most pressing
challenges in order to rapidly advance the project to the next milestone. (a) Paul, S. M.; Mytelka, D. S.;
Dunwiddie1, C. T.; Persinger, C. C.; Munos, B. H.; Lindborg, S. R.; Schacht, A.L. Nature Rev. Drug Discov.
2010, 9, 203-214. (b) Milligan, P. A.; Brown, M. J.; Marchant, B., Martin S. W.; van der Graaf, P. H.;
Benson, N.; Nucci, G.; Nichols, D. J.; Boyd, R. A.; Mandema, J. W.; Krishnaswami, S.; Zwillich, S.; Gruben,
D.; Anziano, R. J.; Stock, T. C.; Lalonde, R.L. Clin. Pharmacol. Ther. 2013, 93, 502-514.
10 Attempts to perform the reductive amination in CH2Cl2 for efficient telescope into the next step were
unsuccessful.
11 The use of iminodiacetic acid (MDA) derived boronate esters to further enhance the regioselectivity
in the acid catalyzed Friedel-Crafts cyclization will be included in a future publication. Gonzalez-Bobes,
F.; Conlon, D. A.; Lobben, P. C.; Burt, J. L.; Engstrom, J.; Wei, C. S.; Zhu, J. J.; Yu, F. Method for the
Preparation of Tetrahydroisoquinomies. (2014), WO 2014159501 A2 20141002.
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Organic Process Research & Development
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12 Other Bronsted acids were explored. MeSO3H was chosen due to its optimal performance in the
reaction, easy of handling and work-up.
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13 (a) Cherylline, a 4-phenyl-1,2,3,4-tetrahydroisoquinoline alkaloid was isolated over 40 years ago as
the DTTA salt. Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey, D. T. J. Org. Chem. 1970, 35
1100-1104. (b) Brossi, A.; Teitel, S. J. Org. Chem. 1970, 35, 3559-3561. (c) Baxter, C. A.; Cleator, E.;
Brands, K. M. J.; Edwards, J. S.; Reamer, R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.; Wallace, D.J.
Org. Process Res. Dev. 2011, 15, 367-375.
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14 (a) Prat, L.; Mojovic, L., Levacher, V., Dupas, G., Quéguiner, G., Bourguignon, J. Tetrahedron:
Asymmetry 1998, 9, 2509-2516. (b) Quallich, G. J. Chirality 2005, 17, S120-S126.
15 Bases such as pyridine and DIPEA were ineffective for this transformation.
16 (a) Wei, C. S.; Davies, G. H. M.; Soltani, O.; Albrecht, J.; Gao, Q.; Pathirana, C.; Hsiao, Y.; Tummala, S.;
Eastgate, M. D. Angew. Chem.; Int. Ed. 2013, 52, 5822 –5826. (b) Hong, J.-H.; Davidson, J. P. ; Jin, Q.;
Lee, G. R.; Matchett, M.; O’Brien,E.; Welch, M.; Bingenheimer, B.; Sarma, K. Org. Process Res. Dev.,
2014, 18, 228–238. (c) Miyura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
17 Anderson, N. G. Practical Process Research and Development, Academic Press:ꢀ New York. 2000.
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Compound 17 was prepared via the slow addition of Boc2O to a solution of the 6-chloropyridazin-3-
amine and DMAP in DMF while maintaining batch temperature at 55 °C. After an inverse quench and
filtration, the product is obtained as a light grey solid in 80% yield (90-97% purity).
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