Process Optimization for the Large-Scale Preparation of (2 S,3 aR,7 aS)- tert-Butyl Hexahydro-2,5-methanopyrrolo[3,2- c]pyridine-1(4 H)-carboxylate, an Intermediate for Nicotinic Acetylcholine Receptor Agonists

Article abstract of DOI:10.1021/acs.oprd.8b00208

An optimized large-scale synthesis of (2S,3aR,7aS)-tert-butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate (1A), an important intermediate for nicotinic acetylcholine receptor agonists, is described. The key feature of the synthesis involves three transformations in a one-pot process, including debenzylation and ring hydrogenation of two fused bicyclic rings. Multihundred gram quantities of 1A were prepared.

Full text of DOI:10.1021/acs.oprd.8b00208

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Full Paper
Process Optimization for Large Scale Preparation of (2S,3aR,7aS)-tert-
Butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate,
an Intermediate for Nicotinic Acetylcholine Receptors Agonists
Lokesh Babu Jarugu, China Anki Reddy, Nanjundaswamy Kanikahalli Chikkananjunda, Suresh
Krishnamoorthy, Pon Sarvanakumar, Ulaganathan Sankar, Pirama Nayagam Arunachalam,
Ivar M. McDonald, Richard E. Olson, Richard A. Rampulla, Arvind Mathur, and Anuradha Gupta
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00208 • Publication Date (Web): 28 Aug 2018
Downloaded from http://pubs.acs.org on August 29, 2018
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Process Optimization for Large Scale Preparation of
(2S,3aR,7aS)ꢀtertꢀButyl hexahydroꢀ2,5ꢀ
methanopyrrolo[3,2ꢀc]pyridineꢀ1(4H)ꢀcarboxylate,
an Intermediate for Nicotinic Acetylcholine
Receptors Agonists
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Lokesh Babu Jarugu, † China Anki Reddy, † Nanjundaswamy Kanikahalli Chikkananjunda, †
Suresh Krishnamoorthy, † Pon Sarvanakumar, † Ulaganathan Sankar, † Pirama Nayagam
Arunachalam, † Ivar M McDonald, ‡ Richard E Olson ‡ Richard Rampulla, ‡ Arvind Mathur ‡ and
Anuradha Gupta* †
†Department of Discovery Synthesis, Biocon BristolꢀMyers Squibb Research Centre, Biocon
Park, Bommasandra IV phase, Jigani Link Road, Bengaluru – 560099, India
‡Bristol Myers Squibb Company, P.O Box 4000, Princeton, New Jersey 08543ꢀ4000, United
States
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ABSTRACT
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An optimized large scale synthesis of (2S,3aR,7aS)ꢀtertꢀbutyl hexahydroꢀ2,5ꢀ
methanopyrrolo[3,2ꢀc]pyridineꢀ1(4H)ꢀcarboxylate (1A), an important intermediate of nicotinic
acetylcholine receptors agonists, is described. The key feature for the synthesis involved three
transformations in a oneꢀpot process including debenzylation and ring hydrogenation of two
fused bicyclic rings. Multi hundred gram quantities of 1A were prepared.
KEYWORDS
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Iodination, Sonogashira coupling, debenzylation, hydrogenation
INTRODUCTION
(2S,3aR, 7aS)ꢀtertꢀbutyl hexahydroꢀ2,5ꢀmethanopyrrolo[3,2ꢀc]pyridineꢀ1(4H)ꢀcarboxylate
(1A) is a key intermediate for tricyclic compounds (Figure 1) identified as potent α7 nicotinic
acetylcholine receptor ligands, which may be useful for the treatment of various disorders of the
central nervous system which are potentially neurodegenerative disorders such as
schizophrenia.1,2
Figure 1. Intermediate 1A and general structure of α7 nicotinic receptor agonists
The medicinal chemistry route1,2 to compound 1A consisted of 10 steps including a SFC chiral
separation starting from tꢀbutyl (3ꢀiodopyridinꢀ4ꢀyl)carbamate 5 (Scheme 1). To support the
preparation of a drug candidate, 200 grams of the advanced intermediate 1A was required.
Based on the reported yields, the calculations indicated requiring > 14 kg of intermediate 5, 7 kg
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of intermediate 8, 2 kg of PtO2 and 1.5 kg of Pd(OH)2 respectively. The original route was used
for synthesizing few hundred milligrams to a gram of 1A for initial studies, however,
synthesizing multi hundred grams following the original route posed some challenges: (1)
expensive and not readily available starting materials such as tꢀbutyl (3ꢀiodopyridinꢀ4ꢀ
yl)carbamate (5) (>$100/g) and ((propꢀ2ꢀynꢀ1ꢀyloxy)methyl)benzene (15), (2) low
reproducibility for the debenzylation and ring reduction and (3) use of expensive PtO2 for this
conversion. This led to the optimization of the original route to a more scalable and economical
process. The current article describes the streamlined large scale synthesis of 1A featuring a
more efficient one step debenzylation and reduction of pyrrolo[3,2ꢀc] pyridine 8 which is the key
step leading to 1A
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Scheme 1: Medicinal chemistry route to 1A
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RESULTS AND DISCUSSION
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Synthesis and optimization of 5 and 15. Due to an aggressive timeline and long lead time
for both the starting material 5 and 15 it was decided to scale up inꢀhouse to jump start the
synthesis. tꢀButyl (3ꢀiodopyridinꢀ4ꢀyl)carbamate (5) was synthesized from inexpensive and
readily available 4ꢀaminopyridine (2) following a known literature procedure3 (Scheme 2).
Iodination of 2 with iodine gave a mixture of undesired 3,5ꢀdiiodoꢀ4ꢀaminopyridine (3) and 3ꢀ
iodoꢀ4ꢀaminopyridine (4) in a ratio of 6:4 as expected. Compound 4 was obtained in only 34%
after a tedious chromatographic separation. This procedure was not conducive to scale up owing
to low yield and selectivity.
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Scheme 2: Optimization of Iodination
Iodine monochloride (ICl) in acetic acid is reported4 to give higher selectivity and yield
though the reaction required over 10 days for completion at temperature around 40 ꢀ 45 oC. It
was envisioned that the reaction time could be shortened by using a combination of higher
temperature and nonꢀreactive acid instead of acetic acid which potentially could react with amine
to form the corresponding acetamide. Initial attempts using iodine monchloride and a catalytic
amount of hydrochloric acid or sulfuric acid at 27 oC yielded negligible amounts of product.
However, by heating the reaction mixture to higher temperatures (100 oC) using 4 equivalents of
methanesulfonic acid the reaction went to completion within 12 h giving almost exclusively
mono iodinated product 4. On a 100 g scale, the reaction yielded desired monoꢀiodo compound
4 in 75% yield with formation of the diꢀiodo product 3 in 1.6%. Reducing methanesulfonic acid
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to two equivalents resulted in prolonged reaction time (24 h), with no apparent change in yield.
The optimized procedure for large scale iodination of 4ꢀaminopyridine (2) was performed using
iodine monochloride and methanesulfonic acid at 100 oC for 12 h. Up to 600 g of 2 was
converted in a single batch and the product 4 was isolated in 75% yield with 96% purity after
trituration in petroleum ether. Intermediate 4 was converted to the corresponding Bocꢀderivative
in 85% isolated yield after a flash chromatography. This procedure was reproduced for a number
of large batches and > 9 Kg of intermediate 5 was synthesized in high yields.
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Scheme 3: Synthesis of benzyl propargyl ether (15)
((propꢀ2ꢀynꢀ1ꢀyloxy)methyl)benzene (15) was synthesized from propargyl alcohol with
benzyl bromide following a literature procedure5 using sodium hydride in DMF. Compound 15
was obtained in moderate yields and involved a tedious workꢀup and column chromatography to
isolate the desired compound. This seemed to be not scalable owing to safety reasons as well as
the issue with isolation. NaH in DMF can result in a thermal runaway reaction which is well
known in literature, especially on larger scale. Following another literature procedure6 (a), (b)
using KOH and DMSO, compound 15 was synthesized in almost quantitative yield. This
reaction work up was easier to handle and required a simple filtration through a silica gel pad
/column giving a quantitative conversion which was better suited for scale up operations. With
these modifications, > 5 kg of 15 was synthesized in excellent yields (Scheme 3).
Optimization of Sonogashira Coupling and subsequent cyclization. Having successfully
synthesized both intermediates in house, the focus turned to the synthesis of the azaindole 8
(Scheme 4). This involved an intermolecular Sonogashira coupling of tꢀbutyl (3ꢀiodopyridinꢀ4ꢀ
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yl)carbamate (5) with ((propꢀ2ꢀynꢀ1ꢀyloxy)methyl)benzene (15) in a pressure tube to get
intermediate 8 in good yield (Scheme 1). From the initial route it was obvious that the use of
pressure tube was not amenable for scaling up hundreds of grams in several batches.
Considering this limitation, it was decided to use thermal condition to ease out scalability issue
of this step.
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Scheme 4: Optimization of Sonogashira coupling for synthesis of intermediate 8
The scheme above describes the optimization efforts for Sonogashira reaction. Following the
medicinal chemistry procedure, an early attempt using reflux conditions, led to the formation of
an unꢀcyclized intermediate tꢀbutyl (3ꢀ(3ꢀ(benzyloxy)propꢀ1ꢀynꢀ1ꢀyl)pyridinꢀ4ꢀyl)carbamate (6)
after 12 h under reflux conditions. Attempts to cyclize compound 6 with DBU in a mixture of
MeOH and H2O at 60 oC resulted in loss of Bocꢀprotecting group to form 7, which further
required Bocꢀprotection to give intermediate 8. This was realized to be a handicap for the scale
up and led to further investigation. When the reaction mixture was heated using a round bottom
flask to 65 °C, LCMS showed the absence of starting material 5 along with 25% formation of
intermediate 6 and 70% formation of desired intermediate 8 after 12 h. A further heating for
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another 12 h, led to a complete conversion to desired intermediate 8. Thus a fine balance of
lowering the reaction temperature to 65 oC and increasing the reaction time to 24 h led to a
complete conversion to 8 in excellent yields. Thus the optimized conditions of Sonogashira
coupling7 involved heating the intermediate 5 at 65 oC in the presence of CuI, Pd(PPh3)2Cl2 and
TEA in DMF for 24 h to afford intermediate 8 in 97% yield. The reaction was scaled up to > 2
Kg in a single batch with reproducible yields and a total of 8 kg was synthesized following
modified procedure.
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Optimization of debenzylation and ring reduction: The most challenging and the key step
in the synthesis towards 1A was the tandem debenzylation and reduction of intermediate 8 to the
completely saturated bicyclic core 9C. The original procedure for reduction of intermediate 8 to
9C involved use of Pd(OH)2 for debenzylation and double bond reduction followed by use of
PtO2 for complete ring reduction. The initial pilot batches following the original experimental
was found to be very confusing and inconsistent in terms of conversion rate going from
compound 9A to 9C via 9B as well as time taken for each batch. A pilot reaction on 10 g (0.03
moles) of compound 8 and 8.23 g of 20 % w/w Pd(OH)2 (on activated carbon 50% wet, 0.06
moles) at an ambient temperature in EtOH in an autoclave for 48 h gave 33% of 9A and 64% 9B
and did not progress any further as function of time. A reꢀcharge (filtration of the reaction
mixture and concentration) of the reaction mixture with fresh solvent and same amount of
Pd(OH)2 took another 48 h for the complete conversion to 9B (Table 1, Entry 1). Surprisingly the
reductive hydrogenation of the crude product 9B using 6.58 g of PtO2 (0.03 moles, 1 equivalent)
in a mixture of EtOH and AcOH at 214 psi pressure did not proceed even at 60 oC (Table 1,
Entry 2). In further reactions, when AcOH alone was used as solvent, 53% of product 9C was
observed over 72 h at 71 psi pressure (Table 1, Entry 3) by LCMS. Notably, an improved yield
was observed when 14.48 g of PtO2 (2.2 equivalents) was used. The procedure provided 93%
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product by LCMS (Table 1, Entry 4). It was concluded that the conversion from 8 to 9C was not
reproducible in terms of time taken as well as yields of the product hence required further
optimization (Table 1).
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Table 1: Optimization effort for conversion of 8 to 9C with variable catalyst loading and
hydrogen pressure
Entry Step
Temp
(°C)
Solvent
Catalyst
Cat.$ H2
(psi)
Time
(h)
Conversion as per
LCMS
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2
8 - 9A to 9B
25
EtOH
Pd(OH)2
Pd(OH)2
PtO2
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33% 9A, 64% 9B
100% 9B
9B to 9C
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60
EtOH+
AcOH
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214
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48
No reaction.
No reaction
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4
9B to 9C
9B to 9C
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AcOH
AcOH
PtO2
PtO2
1
71
71
72
1
53% 9C
93% 9C
2.2
$ Pd(OH)2 20% w/w (50% wet)
Another undesirable aspect of this reduction procedure was also an extremely high catalyst
loading. For example, over a few batches it was observed that for every 1 g of compound 8, it
required Pd(OH)2 20 % w/w 0.6 g and 2 g of PtO2 indicated requiring >1.5 kg Pd(OH)2 and ~2
kg of the PtO2 for the above conversion to obtain ~100 g of intermediate 1A.
With this significant cost concern in mind, it was decided to invest in a cheaper catalyst system
such as Pd/C. During initial optimization, using Pd/C (10% w/w, dry based) it was observed that
5ꢀmembered ring reduction occurred first followed by debenzylation to give the intermediate 9B
and as the reaction progressed, significant amounts of 9B converted to 9C. This looked
promising and it was decided to use Pd/C exclusively for the entire three step reduction process.
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One of the optimization attempts involved a reaction batch of 17 g of 8 (0.05 moles) with 32 g
Pd/C 10% w/w (dry based) at a pressure of 214 psi in ethanol at 60 oC. The batch needed two
recharges each after 48 h and a total of 7 days of reaction time to give the required intermediate
9C in 46.6% yield and indicated further optimization. Similarly weighing and handling of large
quantity of dry Pd/C was also a major concern specially for scaleꢀup batches. At this point it was
decided to use wet Pd/C as a safer alternative to dry Pd/. Fortunately, Pilot runs using 5% w/w
Pd/C (50% wet) gave the same reaction pattern as dry Pd/C in terms of time taken with slightly
higher yields. Further discussion explains the optimization attempts in converting intermediate 8
to 9C via 9A and 9B by varying catalyst loading with function of temperature and time (Table
2). Using 5% w/w Pd/C (50% wet) at 60 oC in an autoclave under 214 psi pressure (Table 2,
Entry 1), formation of 9A (85 %) and 9B (10 %) was observed after 16 h with no significant
improvement after 30 h. At this point the reaction mass was filtered and reꢀcharged with same
quantity of fresh catalyst. The reaction seemed to progress steadily giving predominantly 9B and
9C over a period of 75 h. A 2nd filtration at this point and reꢀcharge using same quantity of Pd/C
led to complete conversion to 9C by 90 h with a crude yield of 53%. These batches on further
scale up were found to be inconsistent in terms of reaction time and % conversion from 8 to 9A,
9B and 9C respectively (Table 2, entry 2). It was concluded that a contaminant in the reaction
vessel might be causing catalyst poisoning.8 As predicted, it was found that preꢀtreating the
reactor with 1N HCl followed by washing with water, MeOH and complete drying greatly
improved conversion rate to 9C from intermediate 8. Following the preꢀtreatment procedure, the
hydrogenation required only one recharge and a total 5 days of reaction time for complete
conversion to 9C (Table 2, Entry 3). This telescopic process consistently led to the desired
intermediate 9C from intermediate 8, requiring only one filtration and one recharge of the
catalyst. Following this procedure, >4 kg of intermediate 9C was synthesized with a maximum
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batch size of 500 g with an average 90% yield. Crude 9C obtained as a mixture of cis and trans
diastereomers was used for the next step without further purification.
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Table 2: Further optimization of hydrogenation step using Pd/C
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Entry Time (h) 9A#
9B#
9C# Remarks
Yield (%)
16
30
54
75
90
85
79
ꢀ
ꢀ
ꢀ
10
18
76
29
ꢀ
ꢀ
ꢀ
1st reꢀcharge here
1
26
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98.5
ꢀ
52.8
2nd reꢀcharge here
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60
100
130
78
15
ꢀ
ꢀ
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ꢀ
1st reꢀcharge
2nd reꢀcharge
3rd reꢀcharge
ꢀ
2
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92.5
58
90
ꢀ
50
ꢀ
54
39
One reꢀcharge
after HCl
treatment
ꢀ
3*
110
ꢀ
ꢀ
96
# = % LCMS monitoring, * = reaction vessel treated with HCl prior to reaction (see text)
End game to intermediate 1A. Compound 9C was converted to the corresponding
diastereomeric mixture of NꢀCbzꢀprotected intermediates which could be separated by flash
chromatography to give the desired racemic intermediate 10(±) in 49% yield (Scheme 5). At this
stage the diastereomeric ratio was found to be 1:1.5, with the major diastereomer bearing the cisꢀ
configuration of hydroxymethyl with the piperidine ring. This single diastereomer of 10 was
further subjected to chiral SFC resolution to give the desired enantiomer 5ꢀbenzyl 1ꢀ(tertꢀbutyl)
(2S,3aR,7aS)ꢀ2ꢀ(hydroxymethyl)hexahydroꢀ1Hꢀpyrrolo[3,2ꢀc]pyridineꢀ1,5(4H)ꢀdicarboxylate
(11A) in 21% overall yield from 9C.
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Scheme 5: Synthesis of compounds 11A and 11 B
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The pure enantiomer 11A thus obtained was treated with tosyl chloride and pyridine to provide
tosylated intermediate 5ꢀbenzyl 1ꢀ(tertꢀbutyl) (2S,3aR,7aS)ꢀ2ꢀ((tosyloxy)methyl)hexahydroꢀ1Hꢀ
pyrrolo[3,2ꢀc]pyridineꢀ1,5(4H)ꢀdicarboxylate (12A) in 92% yield. Intermediate 12A was
deprotected with 10 % w/w Pd/C (50% wet), followed by cyclization with K2CO3 under reflux
conditions to give the final compound (2S,3aR,7aS)ꢀtertꢀbutyl hexahydroꢀ2,5ꢀ
methanopyrrolo[3,2ꢀc]pyridineꢀ1(4H)ꢀcarboxylate (1A) in 78% yield (Scheme 6).
Approximately 250 g of the desired isomer 1A was prepared over multiple batches.
Scheme 6: Synthesis of compound 1A and 1B
Similarly, the other enantiomer 11B obtained during the SFC separation of compound 10 was
converted to tosyl intermediate 12B followed by 1B which was used as a reference.
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CONCLUSION
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In summary, an improved large scale synthesis of (2S,3aR,7aS)ꢀtertꢀbutyl hexahydroꢀ2,5ꢀ
methanopyrrolo[3,2ꢀc]pyridineꢀ1(4H)ꢀcarboxylate (1A) was demonstrated starting from readily
available and inexpensive starting material 2 over 10 steps in an overall yield of 14% for single
enantiomer 1A. The optimized synthesis involved a high yielding and selective monoꢀiodination
of 4ꢀaminopyridine (2), a scalable preparation of benzyl propargyl ether (15), an improved oneꢀ
pot Sonogashira coupling and cyclization to form pyrrolo[3,2ꢀc]pyridine 8. We also identified a
safer and a scalable hydrogenation sequence for the transformation of 8 to debenzylated tertꢀ
butyl 2ꢀ(hydroxymethyl)octahydroꢀ1Hꢀpyrrolo[3,2ꢀc]pyridineꢀ1ꢀcarboxylate (9C).
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EXPERIMENTAL
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Tert-butyl 2-(hydroxymethyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (9C). In a
10 L autoclave reactor, to a stirred solution of tertꢀbutyl 2ꢀ((benzyloxy)methyl)ꢀ1Hꢀpyrrolo [3,2ꢀ
c] pyridineꢀ1ꢀcarboxylate (8) (350 g, 1.03 mol) in ethanol (5.5 L) was added 5% w/w Palladium
on carbon (50% wet) (700 g, 3.29 mol) under nitrogen atmosphere at room temperature. The
reaction mixture was stirred at 60 °C under 214 psi of hydrogen pressure for 50 h. After 12 h
LCMS indicated ~ 39% of intermediate 9C and 54% of intermediate 9B. At this point the
reaction mixture was unloaded and filtered through a celite bed. The celite bed was washed with
500 mL of 5% triethylamine in methanol and the combined filtrate was concentrated. The
residue (265 g) was dissolved in ethanol (5.5 L) and reꢀcharged with 5% w/w palladium on
carbon (50% wet) (700 g, 3.29 mol) under nitrogen atmosphere at room temperature. The
reaction mixture was stirred at 60 °C under 214 psi of hydrogen pressure for 48 h with periodic
monitoring for the full conversion to 9C. The reaction mixture filtered through celite bed and
washed with 500 mL of 5% triethylamine in methanol repeatedly. The filtrate was concentrated
to give the crude product 242 g (90%) as a light brown viscous liquid which was moved to next
step as such. LCMS (ESꢀAPCI) for C13H24N2O3, [M+H]+ calcd. 256.18; found, 257.
5-benzyl 1-(tert-butyl) (2S,3aR,7aS)-2-(hydroxymethyl)hexahydro-1H-pyrrolo[3,2-
c]pyridine-1,5(4H)-dicarboxylate (11A). To a stirred solution of tertꢀbutyl 2ꢀ
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(hydroxymethyl)octahydroꢀ1Hꢀpyrrolo[3,2ꢀc]pyridineꢀ1ꢀcarboxylate (9C) (380 g, 1.48 mol) in
THF (5.03 L) was added 10% potassium carbonate (0.67 kg, 48.47 mol, 6.7 L) and
benzylchloroformate (444 mL, 3.11 mol) in a 10 L autoclave. After 3 h, the reaction mixture was
filtered through celite, concentrated and extracted with ethyl acetate (3 × 2 L). The total organic
layer was washed with water (2 L) followed by brine solution (2 L). The organic layer was dried
over sodium sulfate, filtered and concentrated under reduced pressure. The diastereomeric
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mixture was purified by flash column chromatography using EtOAc as an eluent. The less polar
diastereomer fractions were concentrated to get 288 g of the desired diastereomer 10 which was
separated on SFC to give (124 g, 21.6%) of desired enantiomer 11A as a pale viscous liquid.
[α]25D = +20.6 (c = 0.56, MeOH), 1H NMR (300 MHz, DMSOꢀd6) δ 7.28 ꢀ 7.42 (m, 5H), 5.08 (s,
2H), 4.71 ꢀ 4.79 (m, 1H), 3.34 ꢀ 3.98 (m, 6H), 3.1 ꢀ 3.3 (m, 1H), 2.6 ꢀ 2.9 (m, 1H), 2.1 ꢀ 2.3 (m,
1H), 1.70 ꢀ 1.93 (m, 3H), 1.43 ꢀ 1.62 (m, 1H), 1.39 (s, 9H); LCMS (ESꢀAPCI) for C21H30N2O5,
[MꢀH]ꢀ calcd. 390.22; found, 389.
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Chiral Purity: > 99%, RT: 3.39, Method: Ethanol, Chiralpak ADꢀH (250 x 4.6) mm 5µ.
5-benzyl 1-(tert-butyl) (2S,3aR,7aS)-2-((tosyloxy)methyl)hexahydro-1H-pyrrolo[3,2-
c]pyridine-1,5(4H)-dicarboxylate (12A). To a stirred solution 5ꢀbenzyl 1ꢀ(tertꢀbutyl)
(2S,3aR,7aS)ꢀ2ꢀ(hydroxymethyl)hexahydroꢀ1Hꢀpyrrolo[3,2ꢀc]pyridineꢀ1,5(4H)ꢀdicarboxylate
(11A) (70 g, 0.18 mol) in pyridine (0.84 L) in a 3 L multiꢀneck round bottom flask equipped with
a nitrogen outlet, tosyl chloride (75 g, 0.39 mol) was added portion wise at room temperature
and stirred overnight. The reaction mixture was concentrated completely under reduced pressure.
The residue was dissolved in water (800 mL) and extracted with ethyl acetate (3 × 500 mL). The
organic layer was washed with 1.5 N HCl solution (2 × 500 mL) followed by brine solution (500
mL) and dried over sodium sulfate. This was filtered and concentrated under reduced pressure
and purified using flash column chromatography using EtOAcꢀPet ether as the eluent to yield
1
compound 12A (91.5 g, 92%) as a pale viscous liquid. H NMR (400 MHz, DMSOꢀd6) δ 7.71 ꢀ
7.77 (m, 2H), 7.44 ꢀ 7.49 (m, 2H), 7.31 ꢀ 7.41 (m, 5 H), 5.04 ꢀ 5.15 (m, 2H), 4.00 ꢀ 4.14 (m, 2H),
3.76 ꢀ 3.93 (m, 4H), 3.1 ꢀ 3.2 (m, 1H), 2.64 ꢀ 2.69 (m, 1H), 2.38 ꢀ 2.42 (m, 3H), 2.2 (m, 1H), 1.82
ꢀ 1.96 (m, 1H), 1.52 ꢀ 1.82 (m, 2H), 1.23 ꢀ 1.41 (m, 10H); LCMS (ESꢀAPCI) for C28H36N2O7S,
[M+H]+ ꢀ100 calcd. 544.22; found, 445.
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(2S,3aR,7aS)-tert-butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate
(1A). To a stirred solution of 5ꢀbenzyl 1ꢀ(tertꢀbutyl) (2S,3aR,7aS)ꢀ2ꢀ
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((tosyloxy)methyl)hexahydroꢀ1Hꢀpyrrolo[3,2ꢀc]pyridineꢀ1,5(4H)ꢀdicarboxylate (12A) (128 g,
0.23 mol) in dry ethanol (3 L) in 10 L autoclave was added 10% w/w palladium on carbon (42.5
g, 0.04 mol, 50 % wet) under nitrogen atmosphere. The reaction mass was stirred at room
temperature at 57 psi hydrogen pressure. After 3 h the reaction mixture was filtered through
celite and washed with dry ethanol. To the filtrate was added potassium carbonate (162 g, 1.17
mol) and the mixture was heated to 75 °C for 12 h around which time the reaction was found to
be completed based on LCMS monitoring. The reaction mass was concentrated and diluted with
water (300 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layer
was dried over sodium sulfate, filtered and concentrated to give 44 g (78% yield) of the
compound 1A as off white solid. [α]25D = +42.6 (c = 1.00, MeOH), 1H NMR (400 MHz, DMSOꢀ
d6) δ 3.98ꢀ4.06 (m, 1H), 3.87 ꢀ 3.97 (m, 1H), 3.11 ꢀ 3.21 (m, 1H), 2.87 (m, 1H), 2.59 (m, 4H),
2.22 ꢀ 2.35 (m, 1H), 1.91 ꢀ 2.13 (m, 1H), 1.45 ꢀ 1.79 (m, 3H), 1.36 ꢀ 1.43 (m, 9H); GCMS: (ESI)
for C13H22N2O2, [M+H]+ calcd. 238.17; found, 238; Chiral Purity: 100%, RTꢀ 5.73 min, Method:
0.2% NH4OH in Methanol, Chiralpak IC (250 x 4.6) mm 5µ.
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SUPPORTING INFORMATION
Supporting Information contains experimental and analytical data for the intermediates 4, 5,
15, 8, 11B, 12B and 1B and the analytical data for the compounds 9C, 11A, 12A and 1A.
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AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail: anuradha.gupta@syngeneintl.com.
ACKNOWLEDGMENT
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Authors are extremely grateful to Dr. Jianqing Li BMS for his valuable suggestions and proof
reading the manuscript. Authors are also thankful to Discovery Analytical Department, Biocon
BristolꢀMyers Squibb Research Centre (BBRC), Syngene, Bangalore (India) for Analytical
support.
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