A scalable synthesis of an azabicyclooctanyl derivative, a novel DPP-4 inhibitor

Article abstract of DOI:10.1021/jo801830x

(Chemical Equation Presented) A practical synthetic strategy to a chiral azabicycclooctanyl derivative (1), a potent DPP-4 inhibitor, starting from a commercially available nortropine is described. The stereogenic center of 1 was established employing a modified protocol of Ellman's diastereoselective addition of a benzylic nucleophile to tert-butanesulfinimine. Other key steps include Corey-Chaykovsky reaction, Meinwald rearrangement, and CDMT-promoted amide bond formation involving a sterically hindered amine 2.

Full text of DOI:10.1021/jo801830x

A Scalable Synthesis of an Azabicyclooctanyl Derivative, a Novel
DPP-4 Inhibitor
Zhongbo Fei,† Quanbing Wu,† Fei Zhang,† Yudong Cao,† Chuanqin Liu,†
Wen-Chung Shieh,*,‡ Song Xue,‡ Joe McKenna,‡ Kapa Prasad,*,‡ Mahavir Prashad,‡
Daniel Baeschlin,§ and Kenji Namoto§
Chemical and Analytical DeVelopment, Suzhou NoVartis Pharma Technology Co. Ltd, Changshu, Jiangsu,
China 215537, Chemical and Analytical DeVelopment, NoVartis Pharmaceuticals Corporation, East
HanoVer, New Jersey 07936, and Center for Proteomic Chemistry, NoVartis Institutes for Biomedical
Research, Basel, Switzerland CH-4002
wen.shieh@noVartis.com
ReceiVed August 21, 2008
A practical synthetic strategy to a chiral azabicycclooctanyl derivative (1), a potent DPP-4 inhibitor,
starting from a commercially available nortropine is described. The stereogenic center of 1 was established
employing a modified protocol of Ellman’s diastereoselective addition of a benzylic nucleophile to tert-
butanesulfinimine. Other key steps include Corey-Chaykovsky reaction, Meinwald rearrangement, and
CDMT-promoted amide bond formation involving a sterically hindered amine 2.
Introduction
Our strategy for the synthesis of 1 is outlined in Scheme 1,
involving an attempt to assemble the target molecule by the
condensation of bicyclic amine 2 with acid 3. To establish the
stereogenic center of 2, we considered the asymmetric addition
of a benzylic nucleophile to tert-butanesulfinimine 4, a meth-
odology developed by Ellman.3 Azabicyclooctanyl aldehyde 5,
the precursor to aldimine 4, could be synthesized from a
commercially available starting material bearing the required
azabicyclic skeleton.
Dipeptidyl peptidase 4 (DPP-4) is a clinically validated target
for regulating glycemia. Inhibiting DPP-4 will lead to a
reduction in elevated blood glucose levels (hyperglycemia) that
is a characteristic feature of type 2 diabetes.1 Galvus (Novartis)
and Januvia (Merck), both functioning as DPP-4 inhibitors, have
been approved in several countries for the treatment of type 2
diabetic patients. Compound 1 was identified as another novel
and potent DPP-4 inhibitor at Novartis.2 To assess its efficacy
and safety in man, we needed to develop a commercially viable
route for the production of the active pharmaceutical ingredient
for diabetic clinical trials.
Results and Discussion
Synthesis of Azabicyclooctane Aldehyde. The first route we
considered for the synthesis of aldehyde 9 is shown in Scheme
2. Tropinone 6 was concomitantly protected and demethylated
to afford 7 in 51% yield. Wittig olefination of 7 furnished enol
† Suzhou Novartis Pharma Technology Co. Ltd.
‡ Novartis Pharmaceuticals Corporation.
§ Novartis Institutes for Biomedical Research.
(1) Drucker, D. J. Diabetes Care 2007, 30 (6), 1335–1343.
(2) Baeschlin, D. K.; Fenton, G.; Namoto, K.; Ostermann, N.; Sedrani, R.;
Sirockin, F. Chem. Abstr. 2007, 147, 448757; WIPO, WO 2007/115821.
(3) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913–
9914.
9016 J. Org. Chem. 2008, 73, 9016–9021
10.1021/jo801830x CCC: $40.75 2008 American Chemical Society
Published on Web 10/14/2008

Synthesis of an Azabicyclooctanyl DeriVatiVe
SCHEME 1. Retrosynthetic Analysis of 1
SCHEME 4. Addition of Grignard Reagent to Imine 15
TABLE 1. Influence of Solvent and Temperature on
Diastereoselectivity
SCHEME 2. Initial Route for Aldehyde 9
entry
solvent
temp (°C)
17a:17b
1
2
3
4
5
6
7
Et2O
MeOCH2CH2OMe
toluene
THF
CH2Cl2
25
25
25
25
25
10
-78
40:60
45:55
48:52
42:58
55:45
62:38
70:30
CH2Cl2
CH2Cl2
This route with an overall yield of 75% was employed for our
large scale production of 9.
SCHEME 3. Preferred Route to Aldehyde 9
Grignard Addition to tert-Butanesulfinimine. Two meth-
odologies were investigated for the condensation of aldehyde
9 with (S)-tert-butanesulfinamide 14 (Scheme 4). Under homo-
geneous conditions, Ti(OEt)4 was employed as both Lewis acid
and water scavenger6 affording 15 as a solid in 92% yield
(HPLC purity 97%). Under heterogeneous conditions where
pyridinium-p-toluenesulfonate and magnesium sulfate were
utilized as a catalyst and as a water scavenger, respectively, 15
was obtained in 80% yield. Although the yield of the latter
approach is slightly lower, it is the one adopted for scale-up.
To explore the diastereoselectivity of 1,2-addition of Grignard
reagent 16 to tert-butanesulfinimine 15, we decided to prepare
16 from tri-fluorobenzyl bromide and magnesium turnings in
diethyl ether (Ellman utilized a 3.0 M solution of Grignard
reagent in Et2O in his protocol7). Grignard reagent 16 was then
added to a solution of aldimine 15 in methylene chloride at 25
°C and resulted in the formation of a diastereomeric mixture of
17a and 17b (55:45). The desired 17a was separated from 17b
in 30% yield by chromatography, which was a difficult operation
due to the closeness of their Rf values. To improve the
diastereoselectivity, solvent and temperature effects were probed
and results were outlined in Table 1. The Grignard reagent was
generated in ethyl ether and then added to the solution of 15 in
a variety of solvents at 25 °C. The selectivity was better in a
relative sense when methylene chloride was used (Table 1, entry
5). By lowering the addition temperature from 25 to -78 °C,
an improved selectivity of 17a over 17b was observed (entries
ether 8 in 95% yield. Hydrolysis of 8 with aqueous HCl solution
furnished 9 in 98% yield. Although yields of the last two steps
were excellent, a tedious procedure that was needed to remove
triphenylphosphine oxide byproduct discouraged us from using
this method on a large scale. As a result, an alternative route
according to Scheme 3 was developed.
Treating commercially available nortropine 10 with Cbz-Cl
in the presence of sodium hydroxide afforded alcohol 11 as a
white crystalline solid in 90% yield. Oxidation of 11 with a
catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
in the presence of aqueous sodium hypochlorite solution cleanly
generated ketone 7 in quantitative yield. Epoxidation of 7
employing Corey-Chaykovsky reaction4 provided epoxide 12
as an oil in 90% yield. Meinwald rearrangement5 of 12 with
BF3-OEt furnished a mixture of isomers 9 and 13 (8:1). This
mixture was treated with DBU at rt for 1 h and the thermody-
namically more stable 9 was obtained in 93% isolated yield.
(4) Corey, E. J.; Chaykovsky, M. J. J. Am. Chem. Soc. 1962, 84, 867–868.
(5) Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc. 1963, 85,
582–585.
(6) Ellman, J.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–
995.
(7) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–8904.
J. Org. Chem. Vol. 73, No. 22, 2008 9017

Fei et al.
SCHEME 5. Postulated Transition States of Grignard Addition
SCHEME 6. Deprotection of the Cbz-Protecting Group
5 and 7). The effect of solvent and temperature on diastereo-
selectivity presumably could be explained by transition states
theory postulated in Scheme 5. In a coordinating solvent, such
as diethyl ether, the solvent-Grignard reagent cluster is strongly
stabilized and uncoordinated to the sulfoxide group (pathway
C). As a result, more 16 presumably adds to aldimine 15 from
the sterically less-hindered side leading to 17b as the major
product. At a lower temperature in a noncoordinating solvent,
such as methylene chloride, the chair-form transition state is
postulated to be the favorable one contributing to the formation
of more 17a via pathway A.
Diethyl ether (boiling point 33 °C, flash point -40 °C) is an
unsafe solvent for a manufacturing plant. To replace it with a
safer solvent that could stabilize a Grignard reagent, we prepared
16 in toluene employing 1 equiv of cyclopentyl methyl ether
(CPME) as a stabilizer. CPME is a safer replacement due to its
higher boiling point (101 °C) and flash point (-1 °C). The
resulting Grignard reagent was diluted with methylene chloride
and cooled to -70 °C. A solution of imine 15 in methylene
chloride was added. By employing these conditions (1 equiv
CPME/toluene/CH2Cl2/-70 °C), the selectivity of 17a over 17b
was increased to 85:15, which is superior to that of 70:30 with
Et2O/CH2Cl2/-78 °C conditions (Table 1, entry 7). The
improvement in diastereoselectivity was so significant that we
were able to isolate 17a with high diastereomeric purity (99.8:
0.2 dr) by crystallization of the crude mixture from methanol,
which eliminated expensive and time-consuming chromato-
graphic operations. This process was successfully employed on
plant scales. It is noteworthy that attempts to improve the
stereoselectivity by employing a Lewis acid7 were not fruitful.
The Lewis acids TiCl4, BF3-Et2O, Me3Al, Zn(OTf)2, Mg(OTf)2
were probed, and no significant advantages were found.
Deprotection of Cbz-Protecting Group. Palladium-catalyzed
hydrogenolysis was employed at the outset for the deprotection
of the Cbz group from 17a (Scheme 6) leading to the desired
intermediate 18. Owing to the presence of sulfoxide functionality
in 17a, the reaction needed a large amount of catalyst (two times
the weight of the substrate). Even then, deprotection was still
sluggish. Methansulfonic acid (MSA) was reported as an
efficient reagent for the removal of the Cbz group when it is
used neat.8 It was also documented that other acid-labile
protecting groups, such as Boc or benzyl, could potentially be
cleaved by MSA. We discovered that neat MSA removed the
Cbz group from 17a cleanly without significant impact on the
acid-labile tert-butanesulfinamide group. Under these conditions,
we observed only a small amount (5%) of 19 in crude 18. It is
presumably formed during the quenching process when the
reaction mixture (containing a large excess of MSA) was added
to an aqueous KHCO3 solution. This is supported by the fact
that more 19 was observed if aqueous KHCO3 solution was
(8) Yajima, H.; Kiso, Y.; Ogawa, H.; Fyjii, N.; Irie, H. Chem. Pharm. Bull.
1975, 23, 1164–1166.
9018 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of an Azabicyclooctanyl DeriVatiVe
SCHEME 7. Final Steps
large scale operation, in terms of safety and diastereoselectivity,
employing modified conditions (1 equiv CPME/toluene/CH2Cl2/
-70 °C); (2) the azabicycclooctanyl aldehyde fragment was
established from commercially available nortropine via Corey-
Chaykovsky reaction and Meinwald rearrangement; and (3)
CDMT was demonstrated to be an efficient coupling reagent
for the condensation of sterically hindered, bicyclic amine 18
with acid 3 affording the desired amide in excellent yield and
purity. The optimized synthetic route is economical, efficient,
and incorporated green chemistry principles such as direct
precipitation of the product by the addition of water where
appropriate.
FIGURE 1. Byproducts of the synthesis of 20.
added to the reaction mixture, where more aqueous acid could
be present at the beginning of the quenching. In the optimized
process, pure 18 was precipitated out from the reaction mixture
after a subsequent treatment of the mixture with aqueous NaOH
solution and was isolated as a crystalline solid in 90% yield
(HPLC 99.8:0.2 dr).
Experimental Section
Benzyl
8H-Spiro[8-azabicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate
(12). To a 500-mL, three-necked, round-bottomed flask equipped
with a magnetic stirring bar, a thermometer, and a condenser was
charged THF (anhydrous, 163 mL), potassium tert-butoxide (6.6
g, 95% pure, 55.9 mmol,) and trimethylsulfoxonium iodide
(Me3S+OI-) (13.0 g, 57.9 mmol) under nitrogen atmosphere. The
mixture was heated to reflux and stirred for an additional 3 h. A
solution of 7 (10.0 g, 38.6 mmol) in THF (37 mL) was added in
one portion. The reaction was refluxed for another 2 h. The mixture
was cooled to rt and diluted with toluene (100 mL) and water. The
water layer was separated and extracted with toluene (2 × 50 mL).
The combined organic layers were washed with water (3 × 40 mL)
and evaporated under vacuum to dryness to give 12 (10.6 g, 90%)
as an oil: HPLC assay 95%; 1H NMR (500 MHz, CDCl3) δ
7.38-7.27 (m, 5H), 5.16 (s, 2H), 4.42 (d, J ) 10.4 Hz, 2H), 2.43
(s, 3H), 2.31 (m, 1H), 1.91-2.04 (m, 4H), 1.23 (d, J ) 14.0 Hz,
2H); HRMS calcd for C16H20NO3 [M + H]+ 274.1443, found
274.1433. Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.21; H, 6.90; N, 5.11. HPLC for 7 (tR ) 9.1 min), 12
(tR ) 9.9 min): Agilent Zorbax Eclipse XDB-C18 5 µm 150 mm
× 4.6 mm, flow rate ) 1.0 mL/min, 40 °C, gradient elution from
10:90 A:B to 80:20 A:B over 9 min then held for an additional 3
min (A ) acetonitrile; B ) 0.1% H3PO4).
Final Steps. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)
(21, Scheme 7) was found to be an excellent choice for the
coupling of sterically hindered, bicyclic amine 18 and acid 3 in
the presence of N-methylmorpholine (NMM), affording 20
(HPLC >98%) as a foamy solid in quantitative yield without
any chromatography purifications. The major byproduct, 2-hy-
droxy-4,6-dimethoxy-1,3,5-triazine (22, Figure 1), was easily
removed by aqueous NaHCO3 wash. It is noteworthy that the
order of reagent additions could have significant impact on the
amount of byproduct 23 (Figure 1), which was generated from
the arylation of 18 with CDMT. For instance, when 18, acid 3,
NMM, and CDMT were charged in the order specified, a small
amount (1.5%) of 23 was observed. When the order was
changed to 18, acid 3, CDMT, and NMM, the undesired 23
was increased to 10%.
The last step involves the cleavage of the tert-butanesulfinyl
group from 20. We first followed Ellman’s conditions by treating
20 with HCl in methanol.3 The reaction was clean and fast.
However, we had difficulties in separating byproduct methyl
tert-butanesulfinate from 1 by aqueous workup, due to its poor
hydrophilicity. This problem was easily overcome by cleaving
the tert-butanesulfinyl group with aqueous HCl solution. Under
these conditions, byproduct tert-butanesulfinic acid was com-
pletely removed by aqueous NaOH solution wash. Finally,
crystallization of 1 from isopropyl acetate furnished crystalline
1 (HPLC >99%) as a solid in an overall yield of 80% from 18
over two steps.
Benzyl
3-Formyl-8-azabicyclo[3.2.1]octane-8-carboxylate
(9). To a cold (-3 °C) solution of epoxide 12 (0.5 g, 1.8 mmol) in
THF (anhydrous, 5 mL) was added BF3-OEt2 (120 mL, 0.9 mmol)
under nitrogen atmosphere, maintaining the batch temperature at
<2 °C. The mixture was stirred at 3-5 °C for 3 h. A 5% aqueous
solution of NaHCO3 (5 mL) was added, followed by ethyl acetate
(15 mL). The organic layer was separated, washed with water (2
× 5 mL), and evaporated to dryness. Toluene (5 mL) was added
and evaporated to dryness. The crude product was dissolved in a
solution of THF-MeOH (2.6 mL, 1:1 v/v) and treated with DBU
(14 mg, 0.09 mmol) at rt for 1 h. To the mixture were added 2%
HCl (5 mL) and ethyl acetate (15 mL). The organic layer was
separated, washed with water (5 mL), 2% NaHCO3 (5 mL), and
water (5 mL), and evaporated to dryness. Toluene (5 mL) was added
and evaporated under vacuum to obtain 9 (0.22 g, 80%) as an oil:
IR νmax (KBr) 3033, 2968, 2886, 2814, 2710, 1698, 1416, 1326,
1211, 1101, 1081, 1024 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.55
Conclusion
We disclosed herein a practical synthetic strategy for the
synthesis of an azabicycclooctanyl derivative 1, an active
pharmaceutical ingredient intended to be used in clinical trials
in type 2 diabetes. Some notable features of our synthesis are
as follows: (1) Ellman’s protocol of 1,2-addition of a Grignard
reagent to tert-butanesulfinimine was improved to satisfy our
J. Org. Chem. Vol. 73, No. 22, 2008 9019

Fei et al.
(d, J ) 1.3 Hz, 1H), 7.25-7.40 (m, 5H), 5.16 (s, 2H), 4.45 (br s,
2H), 2.76 (m, 1H), 2.06 (m, 2H), 1.65-1.95 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 202.4, 153.2, 136.6, 128.3, 127.8, 127.7, 66.6,
52.6, 41.7, 30.6, 29.9, 28.3, 27.4. Anal. Calcd for C16H19NO3: C,
70.31; H, 7.01; N, 5.12. Found: C, 70.19; H, 7.34; N, 5.07. HPLC
for 9 (tR ) 3.1 min): Phenomenex Prodigy ODS-2 5 µm C-18 150
mm × 4.6 mm, flow rate ) 1.0 mL/min, 40 °C, isocratic, 65:35
A:B (A ) acetonitrile; B ) 0.05 M NaH2PO4 (pH 2.5)).
layers were combined and solid citric acid was added. (Note:
Approximately 8 g of solid citric acid was used for 1 L of CH2Cl2
solution in order to break the emulsion.) To the mixture was added
water (375 mL) and the resulting mixture was stirred at rt for 10
min. The organic layer was separated and washed with saturated
NaHCO3 (1 × 750 mL) and NaCl (1 × 750 mL). The organic layer
was concentrated to a final volume of 1.5 L and filtered. The filtrate
was evaporated to give a thick orange oil (362 g). To the orange
oil was added warm methanol (40 °C, 1.2 L). The mixture was
stirred at 40-45 °C for an additional 10 min. The solution was
cooled to rt over 30 min. The resulting suspension was cooled to
-15 °C and stirred for an additional 40 min. The solids were
collected by filtration and rinsed with methanol-water (300 mL,
3:2 v/v). The solids were dried under vacuum at 35 °C for 16 h to
give 17a (189 g, 65%) as a white solid: mp 89-92 °C; HPLC assay
>99.5%; IR νmax (KBr) 3472, 3169, 2956, 1701, 1520, 1472, 1447,
Azabicyclooctanyl Imine (15). A 50-mL, three-necked, round-
bottomed flask was charged with aldehyde 9 (1.6 g, 3.6 mmol),
toluene (8 mL), (s)-tert-butanesulfinamide 14 (0.5 g, 3.9 mmol),
pyridine toluenesulfonate (46 mg, 0.18 mmol), and MgSO4 (860
mg, 7.2 mmol) under nitrogen atm. The suspension was stirred at
rt for 16 h. the solids were removed by filtration. The filtrate was
washed with water (2 × 8 mL) and evaporated under vacuum to
dryness. To the suspension were added isopropyl acetate (0.5 mL)
and n-heptane (2 mL). The suspension was filtered to obtain 15
(1.1 g, 80%) as a white solid: mp 77-79 °C; HPLC assay >99%;
IR νmax (KBr) 2974, 2947, 2880, 1697, 1623, 1451, 1405, 1326,
1212, 1100, 1078, 1020 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.90
(d, J ) 4.4 Hz, 1H), 7.29-7.38 (m, 5H), 5.15 (s, 2H), 4.43 (br s,
2H), 2.95-3.05 (m, 1H), 2.01-2.09 (m, 2H), 1.70-1.80 (m, 6H),
1.17 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.5, 153.3, 136.7,
128.4, 127.9, 127.8, 66.6, 56.5, 53.0, 35.6, 33.9, 33.2, 28.3, 27.6,
22.2, 22.0. Anal. Calcd for C20H28N2O3S: C, 63.80; H, 7.50; N,
7.44; S, 8.52. Found: C, 63.52; H, 7.81; N, 7.41; S, 8.53. HPLC
for 9 (tR ) 3.1 min); 15 (tR ) 4.8 min): Phenomenex Prodigy
ODS-2 5 µm C-18 150 mm × 4.6 mm, flow rate ) 1.0 mL/min,
40 °C, isocratic, 65:35 A:B (A ) acetonitrile; B ) 0.05 M NaH2PO4
(pH 2.5)).
Phenylmethyl (3-exo)-3-[(1R)-1-[[(S)-(1,1-Dimethylethyl)-
sulfinyl]amino]-2-(2,4,5- trifluorophenyl)ethyl]-8-azabicyclo-
[3.2.1]octane-8-carboxylate (17a). Magnesium (42 g, 1.8 mol),
iodine (420 mg, 1.6 mmol), and cyclopentyl methyl ether (154 g,
1.54 mol) were charged to a 2-L, four-necked, round-bottomed flask
equipped with a mechanical stirrer, a thermocouple, and an addition
funnel under nitrogen atmosphere. The mixture was stirred at 20-23
°C for 5 min. 2,4,5-Trifluorobenzyl bromide (4.7 g, 20 mmol) was
added over 15 min to initiate the formation of the corresponding
Grignard reagent. After the addition, the mixture was stirred for
an additional 5 min at rt until the iodine color dissipated [Note:
the batch temperature slowly increased and was maintained at
20-28 °C with an ice bath]. Toluene (560 mL) was added to the
mixture. Additional 2,4,5-trifluorobenzyl bromide (310.3 g, 1.4 mol)
was added, maintaining the temperature between 20 and 28 °C with
an ice bath. The mixture was stirred for an additional 30 min at rt
to obtain a gray suspension. [Note: The Grignard reagent formation
was monitored by quenching a sample with water and checked with
HPLC: Phenomenex Ultracarb ODS-30 5 µm C-18 250 mm × 4.6
mm, flow rate ) 1.0 mL/min, 20 °C, isocratic, 65:35 A:B, A )
acetonitrile, B ) water, until the disappearance of 2,4,5-trifluo-
robenzyl bromide, tR ) 10.9 min.] A 12-L, four-necked, round-
bottomed flask equipped with a mechanical stirrer, a thermocouple,
and an addition funnel was charged with anhydrous CH2Cl2 (3.8
L). The solvent was cooled to -78 °C. The freshly prepared solution
of 2,4,5-trifluorobenzylmagnesium bromide in toluene was added
to methylene chloride, while keeping the batch temperature below
-55 °C. The mixture was cooled to -70 °C. A solution of aldimine
15 (210 g, 0.56 mol) in CH2Cl2 (350 mL) was added to the reaction
mixture, while keeping the temperature below -55 °C. The mixture
was allowed to warm to rt over 1.5 h and stirred for an additional
16 h. The reaction was monitored by HPLC until the ratio of 15 to
(17a + 17b) was determined to be <1%. The mixture was cooled
to 10 °C. Saturated NH4Cl solution (1.5 L) was slowly added to
the mixture, while keeping the batch temperature below 18 °C. The
resulting gray emulsion was broken by adjusting the pH to 4.6-5.0
with 20% aqueous citric acid (350 mL). The organic layer
containing product was separated and saved. The aqueous layer
was extracted one more time with CH2Cl2 (375 mL). The organic
1
1330, 1211, 1152, 1094, 1077, 1014 cm-1; H NMR (400 MHz,
CDCl3) δ 7.30-7.40 (m, 5H), 7.15 (m, 1H), 6.95 (m, 1H),
5.05-5.20 (m, 2H), 4.35 (br s, 2H), 3.45 (s, 1H), 3.10-3.30 (m,
2H), 2.81-2.98 (m, 2H), 1.80-2.00 (m, 4H), 1.50-1.70 (m, 4H),
1.17 (s, 9H); MS (ESI) m/z 523.225 (M + H+). Anal. Calcd for
C27H33F3N2O3S: C, 62.05; H, 6.36; N, 5.36; F, 10.91; S, 6.14.
Found: C, 61.96; H, 6.49; N, 5.26; F, 10.88; S, 5.98. HPLC for 15
(tR ) 14.6 min); 17a (tR ) 19.4 min); 17b (tR ) 19.8 min): Alltech
Inertsil ODS-2 5 µm C-18 150 mm × 4.6 mm, flow rate ) 1.0
mL/min, 40 °C, 35:65 A:B 5 min then gradient elution from 35:65
A:B to 65:35 A:B over 10 min (A ) acetonitrile; B ) 0.05 M
NaH2PO4 (pH 2.5)). Chiral HPLC assay 99.8:0.2 er, sample 17a
was treated with aqueous HCl solution to remove the tert-
butanesulfinamide group and the resulting enantiomer was analyzed:
Chiral Technologies Chiralpak AD, 5 µm 250 mm × 4.6 mm, flow
rate)0.6mL/min,20°C,isocratic,2-propanol-hexane-diethylamine
) 20:80:0.1: (S)-enantiomer, tR ) 15.5 min; (R)-enantiomer, tR )
16.4 min. Analytical sample of 17b: mp 137-140 °C; IR νmax (KBr)
3258, 3060, 2956, 1678, 1519, 1462, 1426, 1330, 1207, 1152, 1113,
1
1060 cm-1; H NMR (400 MHz, CDCl3) δ 7.24-7.45 (m, 5H),
7.07 (m, 1H), 6.93 (m, 1H), 5.18 (s, 2H), 4.41 (br s, 2H), 3.20 (m,
2H), 2.75 (d, J ) 14.2 Hz, 1 H), 2.54 (dd, J ) 13.8, 10.1 Hz, 1H),
2.38 (m, 1H), 2.00 (m, 2H), 1.50-1.80 (m, 6H), 1.07 (s, 9H). Anal.
Calcd for C27H33F3N2O3S: C, 62.05; H, 6.36; N, 5.36; F, 10.91; S,
6.14. Found: C, 62.19; H, 6.37; N, 5.30; F, 10.60; S, 5.93.
[S(S)]-N-[(1R)-1-(3-exo)-8-Azabicyclo[3.2.1]oct-3-yl-2-(2,4,5-
trifluorophenyl)ethyl]-2-methyl-2-propanesulfinamide (18). To
a 5-L, round-bottomed flask was charged methanesulfonic acid (1.4
kg, 14.6 mol). While the acid was stirred moderately, 17a (350 g,
0.67 mol) was added in portions (∼6 g each portion) at 19-27 °C
over 60 min [Note: exotherm and evolution of CO2 were observed].
After the addition, the mixture was stirred at 24-27 °C for an
additional 2 h [Note: a mild evolution of CO2 continued during
this period]. The reaction was monitored by HPLC until the ratio
of 17a to (18 + 19) was determined to be <0.5%. The mixture
was quenched in two equal parts. Each part was added to a solution
of KHCO3 (875 g) in H2O (5.25 L) in a 22-L, round-bottomed
flask over a period of 30 min, maintaining both temperature below
25 °C and foaming under control [Note: a 22-L flask was used to
provide large headspace for the vigorous gas evolution that
occurred]. The aqueous layers from the two quenches were
combined and washed with tert-butyl methyl ether (TBME) (2 ×
2.5 L). The aqueous layer was separated and treated with 50% (w/
w) NaOH (445 g) until pH 14 was reached. The mixture was stirred
at rt for 1 h. The solids were collected by filtration, rinsed with
water (3 L), and dried under vacuum at 45 °C for 16 h to afford
amine 18 (234.2 g, 90% yield) as a pinky white solid: mp 114-117
°C; HPLC assay 99%; [R]25D +39.7 (c 1.0, CH3OH); IR νmax (KBr)
3421, 3156, 3057, 2936, 2918, 2304, 1676, 1634, 1521, 1474, 1423,
1323, 1204, 1153, 1056 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.14
(m, 1H), 6.83 (m, 1H), 3.47 (m, 2H), 3.16 (m, 1H), 3.10 (d, J )
8.1 Hz, 1H), 2.75-2.90 (m, 2H), 1.20-1.90 (m, 10H), 1.10 (s,
9H); MS (ESI) m/z 389.188 (M + H+). Anal. Calcd for
9020 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of an Azabicyclooctanyl DeriVatiVe
C19H27F3N2OS: C, 58.74; H, 7.01; N, 7.21; S, 8.25. Found, C, 58.48;
H, 7.12; N, 7.14; S, 8.44. HPLC for 17a (tR ) 6.9 min); 18 (tR )
1.7 min); 19 (tR ) 2.0 min): Alltech Inertsil ODS-2 5 µm C-18
150 mm × 4.6 mm, flow rate ) 1.0 mL/min, 40 °C, isocratic, 65:
35 A:B (A ) acetonitrile; B ) 0.05 M NaH2PO4 (pH 2.5)). HPLC
assay for diastereomeric ratio ) 99.8:0.2: Gemini C18, 3 µm 150
mm × 3.0 mm, flow rate ) 1.0 mL/min, 40 °C, UV 210 nm,
gradient elution from 10:90 A:B to 90:10 A:B over 16 min, held
for an additional 4 min, then to 10:90 A:B over 5 min (A)
acetonitrile; B ) 20 mM NaClO4 in 0.1% (v/v) HClO4). (R,S)-
Diastereomer, tR ) 7.15 min; (S,S)-diastereomer, tR ) 8.05 min.
[S(S)]-N-[(1R)-1-(3-exo)-8-[2-(4-Morpholinylsulfonyl)acetyl]-
8-azabicyclo[3.2.1]oct-3-yl-2-(2,4,5-rifluorophenyl)ethyl]-2-meth-
yl-2-propanesulfinamide (20). To a 2-L, three-necked, round-
bottomed flask equipped with a mechanical stirrer and a thermocouple
was charged 18 (30 g, 77.0 mmol), morpholinosulfonyl acetic acid
3 (17.1 g, 81.0 mmol), ethyl acetate (1.4 L), and N-methylmor-
pholine (15 g, 148 mmol) under nitrogen atmosphere. The mixture
was stirred at rt for 15 min to obtain a hazy solution. To the mixture
was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 20 g, 112
mmol) and the batch was stirred at rt for an additional 3 h. The
mixture was washed with 10% aqueous citric acid (1 × 400 mL),
5% aqueous NaHCO3 (1 × 400 mL), and saturated NaCl (1 × 400
mL). The organic phase was evaporated at 35 °C under vacuum
(70-80 torr) to dryness to obtain 20 (44.2 g, 76.2 mmol, 99% yield)
as a gummy oil: HPLC assay 96%; IR νmax (KBr) 3269, 3047, 2977,
extracted into isopropyl acetate (1 × 400 mL). The organic layer
was separated and washed with 1 N NaOH (1 × 200 mL) and water
(2 × 200 mL). The organic layer was evaporated at 50 °C under
vacuum (110 Torr) until the final volume of 80 mL was obtained.
To the concentrate were added seeds and the batch was stirred at
rt for 1.5 h. The solids were collected by filtration, rinsed with
isopropyl acetate (5 °C, 35 mL), and dried at 50 °C under vacuum
for 16 h to obtain 1 (26.1 g, 72%) as a white solid: mp 117-119
°C; HPLC assay >99%; [R]20D -5.7 (c 1.0, CH3OH); IR νmax (KBr)
3385, 2974, 2959, 2927, 2857, 1643, 1518, 1453, 1422, 1341, 1328,
1
1301, 1235, 1210, 1161, 1124, 1112, 1074, 1044, 1013 cm-1; H
NMR (500 MHz, CDCl3) δ 7.05 (m, 1H), 6.90 (m, 1H), 4.75 (m,
1H), 4.41 (m, 1H), 4.05 (m, 2H), 4.00 (m, 2H), 3.75 (m, 4H), 3.45
(m, 4H), 2.70-2.85 (m, 2H), 2.40 (m, 1H), 2.15 (m, 1H), 1.95 (m,
2H), 1.20-1.85 (m, 8H); 13C NMR (125 MHz, CDCl3, signals
marked with an asterisk correspond to rotamers) δ 156.9, 156.1 (J
) 243 Hz), 148.7 (J ) 242 Hz), 146.6 (J ) 243 Hz), 122.7, 118.7,
105.4, 66.6, 56.3, 55.6, 55.5*, 54.2, 52.0*, 51.9, 46.1, 35.9, 34.5*,
34.49, 34.43*, 34.40, 34.3*, 34.2, 32.8, 28.6*, 28.5, 27.2, 27.1*.
Anal. Calcd for C21H28F3N3O4S: C, 53.04; H, 5.94; N, 8.84; F,
11.99. Found: C, 52.98; H, 5.97; N, 8.81; F, 12.23. HPLC for 20
(tR ) 4.6 min); 1 (tR ) 1.8 min): Phenomenex Prodigy ODS-2 5
µm C-18 150 mm × 4.6 mm, flow rate ) 1.0 mL/min, 40 °C,
isocratic, 50:50 A:B (A ) acetonitrile; B ) 0.05 M NaH2PO4 (pH
2.5)).
2862, 1641, 1519, 1455, 1424, 1348, 1211, 1162, 1114, 1074 cm-1
;
Acknowledgement. We thank Drs. Apurva Chaudhary and
Ming Xu for project guidance and Mr. James Vivelo for
engineering support during the pilot plant campaign. We are
indebted to Mr. Robert DuVal, Dr. Tangqing Li, and Dr.
Michael Girgis for calorimetric studies and discussions on plant
safety. We appreciate analytical assistance from Mr. Stan
Babiak, Dr. Donald Drinkwater, Ms. Sara Kessler, and Ms. Ada
Skorodinsky.
1H NMR (400 MHz, CDCl3) δ 7.21 (m, 1H), 6.93 (m, 1H), 4.72
(m, 1H), 4.37 (m, 1H), 3.85-4.05 (m, 2H), 3.74 (m, 4H), 3.20-3.45
(m, 6H), 2.83-3.00 (m, 2H), 1.42-2.20 (m, 9H), 1.20 (s, 9H);
MS m/z 580.211 (M + H+). Anal. Calcd for C25H36F3N3O5S2: C,
51.80; H, 6.26; N, 7.25; F, 9.83; S, 11.06. Found: C, 51.67; H,
6.49; N, 7.13; F, 9.54; S, 11.15. HPLC for 18 (tR ) 2.7 min); 20
(tR ) 5.5 min): Agilent Zorbax SB-C18 3.5 µm 150 mm × 3.0
mm, flow rate ) 0.3 mL/min, 40 °C, isocratic, 50:50 A:B (A )
acetonitrile; B ) 0.1% TFA).
1-{3-[(R)-1-Amino-2-(2,4,5-trifluorophenyl)ethyl]-8-aza-
bicyclo[3.2.1]oct-8-yl}-2-(morpholine-4-sulfonyl)ethanone (1). To
a 1-L, three-necked, round-bottomed flask equipped with a me-
chanical stirrer and a thermocouple were charged 20 (44.2 g, 76.2
mmol), THF (50 mL), and 6 N aqueous HCl (39 mL) under nitrogen
atm. The mixture was stirred at rt for an additional 30 min. A
solution of 1 N NaOH (400 mL) was added. The product was
Supporting Information Available: Experimental details for
the syntheses of compounds 7 and 11 and copies of 1H and 13
C
NMR spectra for compounds 1, 7, 9, 11, 12, 15, 17a, 17b, 18,
and 20, and HPLC spectra for compound 18. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801830X
J. Org. Chem. Vol. 73, No. 22, 2008 9021